Modulators of toll-like receptors

ABSTRACT

The present application includes novel modulators of TLRs, compositions containing such compounds, therapeutic methods that include the administration of such compounds.

This application is filed under 35 U.S.C, 111(a) claiming the benefitunder 35 U.S.C. 119(e) of U.S. provisional application 61/242,194 filedSep. 14, 2009 which is herein incorporated by reference in its entiretyfor all purposes.

FIELD OF THE INVENTION

This application relates generally to 3-deazapteridinone derivatives andpharmaceutical compositions which selectively modulate toll-likereceptors (such as TLR-7), and methods of making and using suchcompounds.

BACKGROUND OF THE INVENTION

The innate immune system provides the body with a first line defenseagainst invading pathogens. In an innate immune response, an invadingpathogen is recognized by a germline-encoded receptor, the activation ofwhich initiates a signaling cascade that leads to the induction ofcytokine expression. Innate immune system receptors have broadspecificity, recognizing molecular structures that are highly conservedamong different pathogens. One family of these receptors is known asToll-like receptors (TLRs), due to their homology with receptors thatwere first identified and named in Drosophila, and are present in cellssuch as macrophages, dendritic cells, and epithelial cells.

There are at least ten different TLRs in mammals. Ligands andcorresponding signaling cascades have been identified for some of thesereceptors. For example, TLR-2 is activated by the lipoprotein ofbacteria (e.g., E. coli.), TLR-3 is activated by double-stranded RNA,TLR-4 is activated by lipopolysaccharide (i.e., LPS or endotoxin) ofGram-negative bacteria (e.g., Salmonella and E. coli O157:H7), TLR-5 isactivated by flagellin of motile bacteria (e.g., Listeria), TLR-7recognizes and responds to imiquimod (and ssRNA) and TLR-9 is activatedby unmethylated CpG sequences of pathogen DNA. The stimulation of eachof these receptors leads to activation of the transcription factorNF-κB, and other signaling molecules that are involved in regulating theexpression of cytokine genes, including those encoding tumor necrosisfactor-alpha (TNF-α), interleukin-1 (IL-1), and certain chemokines.Agonists of TLR-7

There are a number of diseases, disorders, and conditions linked to TLRssuch that therapies using a TLR agonist are believed promising,including but not limited to melanoma, non-small cell lung carcinoma,hepatocellular carcinoma, basal cell carcinoma, renal cell carcinoma,myeloma, allergic rhinitis, asthma, COPD, ulcerative colitis, hepaticfibrosis, and viral infections such as HBV, HCV, HPV, RSV, SARS, HIV, orinfluenza.

SUMMARY OF THE INVENTION

One aspect of the present invention includes a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

L¹ is —NR⁸—, —O—, —S—, —N(R⁸)C(O)—, —S(O)₂—, —S(O)—, or a covalent bond;

R¹ is H, alkyl, substituted alkyl, haloalkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, heteroalkyl, substitutedheteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl,substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,heterocyclylalkyl, or substituted heterocyclylalkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, arylalkyl, substitutedarylalkyl, heteroarylalkyl, substituted heteroarylalkyl,carbocyclylalkenyl, substituted carbocyclylalkenyl, carbocyclylalkynyl,substituted carbocyclylalkynyl, heterocyclylalkenyl, substitutedheterocyclylalkenyl, heterocyclylalkylyl, substituted heteroalkylyl,arylalkenyl, substituted arylalkenyl, arylalkynyl, substitutedarylalkynyl, heteroarylalkenyl, substituted heteroarylalkenyl,heteroarylalkylyl, substituted heteroarylalkynyl,carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl,heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl,arylheteroalkyl, substituted arylheteroalkyl, heteroarylheteroalkyl, orsubstituted heteroarylheteroalkyl;

Z is H, halogen, alkyl, substituted alkyl, haloalkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl,substituted heteroalkyl, carbocyclyl, substituted carbocyclyl,carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclylalkyl, or substitutedheterocyclylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl,substituted heteroarylalkyl, carbocyclylheteroalkyl, substitutedcarbocyclylheteroalkyl, heterocyclylheteroalkyl, substitutedheterocyclylheteroalkyl, arylheteroalkyl, substituted arylheteroalkyl,heteroarylheteroalkyl, or substituted heteroarylheteroalkyl, cyano,azido, —C(O)H, —C(O)R⁸, —S(O)R⁸, —S(O)₂R⁸, —S(O)₂NR⁸R⁹, —C(O)OR⁸, or—C(O)NR⁹R¹⁰:

each non-hydrogen Z may connect to X¹ to form an additional 5 to 8membered carbocyclic or heterocyclic ring;

X¹ is alkylene, substituted alkylene, heteroalkylene, substitutedheteroalkylene, alkenylene, substituted alkenylene, alkynylene,substituted alkynylene, carbocyclylene, substituted carbocyclylene,heterocyclylene, substituted heterocyclylene, —NR⁸—, —O—, —C(O)—,—S(O)—, —S(O)₂—, or a covalent bond;

D is carbocyclyl, heterocyclyl, aryl, or heteroaryl, bearing an openvalence for the attachment points of each R³ and (L²-R²);

each L² is independently alkylene, substituted alkylene, heteroalkylene,substituted heteroalkylene, alkenylene, substituted alkenylene,alkynylene, substituted alkynylene, carbocycylene, substitutedcarbocyclylene, heterocyclylene, substituted heterocyclylene, arylene,substituted arylene, heteroarylene, substituted heteroarylene,arylene-alkylene, heteroarylene-alkylene, arylene-heteroalkylene,substituted arylene-heteroalkylene, heteroarylene-heteroalkylene,substituted heteroarylene-heteroalkylene, or a covalent bond;

each R² is independently —NR⁶R⁷;

m is 1 or 2;

each R³ is independently alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, halogen, haloalkyl, haloalkoxy,heteroalkyl, substituted heteroalkyl, ═O, —OR⁸, —SR⁸, —NR⁹R¹⁰, ═NR⁸,═NOR⁸, ═NNR⁸R⁹, —CN, —OCN, —SCN, —N═C═O, —NCS, —NO, —NO₂, ═N₂, —N₃,—NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)OR⁸,—OC(═O)NR⁹R¹⁰, —OC(═O)OR⁸, —C(═O)R⁸, —S(═O)₂OR⁸, —S(═O)₂R⁸, —OS(═O)₂OR⁸,—S(═O)₂NR⁹R¹⁰, —S(═O)R⁸, —NR⁸S(═O)₂R⁹, —NR⁸S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂OR⁹,—OS(O)₂NR⁹R¹⁰, —OP(═O)(OR⁸)₂, —P(═O)(OR⁸)₂, —P(O)(OR⁸)(R⁹), —P(O)R⁹R¹⁰,—OP(═))R⁹R¹⁰, —C(═S)R⁸, —C(═S)OR⁸, —C(═O)SR⁸, —C(═S)SR⁸, —C(═S)NR⁹R¹⁰,—C(═NR⁸)NR⁹R¹⁰, or —NR⁸C(═NR⁸)NR⁹R¹⁰;

n is 0, 1, 2, 3, 4 or 5, depending on the size of the depicted ring D,such that sufficient attachment points are present;

R⁴ and R⁵ are each independently H, alkyl, substituted alkyl, haloalkyl,heteroalkyl, substituted heteroalkyl, carbocyclyl, substitutedcarbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclylalkyl, substitutedheterocyclylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl,carbocyclylalkenyl, substituted carbocyclylalkenyl, carbocyclylalkynyl,substituted carbocyclylalkynyl, heterocyclylalkenyl, substitutedheterocyclylalkenyl, heterocyclylalkylyl, substituted heteroalkylyl,arylalkenyl, substituted arylalkenyl, arylalkynyl, substitutedarylalkynyl, heteroarylalkenyl, substituted heteroarylalkenyl,heteroarylalkylyl, substituted heteroarylalkynyl, substitutedheteroarylalkyl, carbocyclyl heteroalkyl, substitutedcarbocyclylheteroalkyl, heterocyclylheteroalkyl, substitutedheterocyclylheteroalkyl, arylheteroalkyl, substituted arylheteroalkyl,heteroarylheteroalkyl, or substituted heteroarylheteroalkyl, cyano,azido, —OH, alkoxy, —C(O)H, —C(O)R⁸, —SR⁸, —S(O)R⁸, —S(O)₂R⁸, —C(O)OR⁸,or ——O(O)NR⁹R¹⁰; or

R⁴ and R⁵, taken together with the carbon to which they are bothattached, form a substituted or unsubstituted 3 to 8 membered carbocycleor heterocycle; or

R⁴ and R⁵, taken together with the carbon to which they are attached,form a —C(═O), —C(═NR⁸), —C(═NOR⁸), or —C(═NNR⁸R⁹);

R⁶ and R⁷ are each independently H, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, haloalkyl,heteroalkyl, substituted heteroalkyl, carbocyclyl, substitutedcarbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclylalkyl, substitutedheterocyclylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl,carbocyclylalkenyl, substituted carbocyclylalkenyl, carbocyclylalkynyl,substituted carbocyclylalkynyl, heterocyclylalkenyl, substitutedheterocyclylalkenyl, heterocyclylalkylyl, substituted heteroalkylyl,arylalkenyl, substituted arylalkenyl, arylalkynyl, substitutedarylalkynyl, heteroarylalkenyl, substituted heteroarylalkenyl,heteroarylalkylyl, substituted heteroarylalkynyl, substitutedheteroarylalkyl, carbocyclyl heteroalkyl, substitutedcarbocyclylheteroalkyl, heterocyclylheteroalkyl, substitutedheterocyclylheteroalkyl, arylheteroalkyl, substituted arylheteroalkyl,heteroarylheteroalkyl, or substituted heteroarylheteroalkyl, —C(O)H,—C(O)R⁸, —S(O)R⁸, —S(O)₂R⁸, —C(O)OR⁸, or —C(O)NR⁹R¹⁰, S(O)₂NR⁹R¹⁰; or

R⁶ and R⁷, taken together with the nitrogen to which they are bothattached, form a substituted or unsubstituted 3 to 8 memberedheterocycle, which may contain one or more additional heteroatomsselected from N, O, S, or P; or

R⁷ taken together with L², and the N to which they are both attached,forms a substituted or unsubstituted 3 to 8 membered heterocycle whichmay contain one or more additional heteroatoms selected from N, O, S, orP; or

R⁷ taken together with D, L², and the N to which both R⁷ and L² areattached forms a substituted or unsubstituted 5 to 15 memberedheterocycle or heteroaryl which may contain one or more additionalheteroatoms selected from N, O, S, or P;

R⁸ is H, alkyl, substituted alkyl, haloalkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, heteroalkyl, substitutedheteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl,substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclylalkyl, substituted heterocyclylalkyl, arylalkyl, substitutedarylalkyl, heteroarylalkyl, substituted heteroarylalkyl,carbocyclylalkenyl, substituted carbocyclylalkenyl, carbocyclylalkynyl,substituted carbocyclylalkynyl, heterocyclylalkenyl, substitutedheterocyclylalkenyl, heterocyclylalkylyl, substituted heteroalkylyl,arylalkenyl, substituted arylalkenyl, arylalkynyl, substitutedarylalkynyl, heteroarylalkenyl, substituted heteroarylalkenyl,heteroarylalkylyl, substituted heteroarylalkynyl,carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl,heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl,arylheteroalkyl, substituted arylheteroalkyl, heteroarylheteroalkyl, orsubstituted heteroarylheteroalkyl; and

R⁹ and R¹⁰ are each independently H, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, haloalkyl,heteroalkyl, substituted heteroalkyl, carbocyclyl, substitutedcarbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl,heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, substitutedheterocyclylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl,substituted heteroarylalkyl, carbocyclylalkenyl, substitutedcarbocyclylalkenyl, carbocyclylalkynyl, substituted carbocyclylalkynyl,heterocyclylalkenyl, substituted heterocyclylalkenyl,heterocyclylalkylyl, substituted heteroalkylyl, arylalkenyl, substitutedarylalkenyl, arylalkynyl, substituted arylalkynyl, heteroarylalkenyl,substituted heteroarylalkenyl, heteroarylalkylyl, substitutedheteroarylalkynyl, carbocyclylheteroalkyl, substitutedcarbocyclylheteroalkyl, heterocyclylheteroalkyl, substitutedheterocyclylheteroalkyl, arylheteroalkyl, substituted arylheteroalkyl,heteroarylheteroalkyl, or substituted heteroarylheteroalkyl; or

R⁹ and R¹⁰, taken together with the atom to which they are bothattached, form a substituted or unsubstituted 3 to 8 memberedheterocycle.

In one embodiment, the present invention includes a compound of FormulaIa:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   L¹ is —NH— or —O—;    -   R¹ is H, alkyl, substituted alkyl, carbocylyl, substituted        carbocyclyl, heterocyclyl, substituted heterocyclyl,        carbocyclylalkyl, substituted carbocyclylalkyl,        heterocyclylalkyl, or substituted heterocycylalkyl;    -   X¹ is alkylene, substituted alkylene, heteroalkylene, or        substituted heteroalkylene;    -   D is aryl or heteroaryl;    -   is 0, 1, or 2;    -   each R³ is independently alkyl, substituted alkyl, alkenyl,        substituted alkenyl, alkynyl, substituted alkynyl, halogen,        haloalkyl, haloalkoxy, heteroalkyl, substituted heteroalkyl, ═O,        —OR⁸, —SR⁸, —NR⁹R¹⁰, ═NR⁸, ═NOR⁸, ═NNR⁸R⁹, —CN, —OCN, —SCN,        —N═C═O, —NCS, —NO, —NO₂, ═N₂, —N₃, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹,        —NR⁸C(═O)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)OR⁸, —OC(═O)NR⁹R¹⁰,        —OC(═O)OR⁸, —C(═O)R⁸, —S(═O)₂OR⁸, —S(═O)₂R⁸, —OS(═O)₂OR⁸,        —S(═O)₂NR⁹R¹⁰, —S(═O)R⁸, —NR⁸S(═O)₂R⁹, NR⁸S(═O)₂NR⁹R¹⁰,        —NR⁸S(═O)₂OR⁹, —OS(O)₂NR⁹R¹⁰, —OP(═O)(OR⁸)₂, —P(═O)(OR⁸)₂,        —P(O)(OR⁸)(R⁹), —P(O)R⁹R¹⁰, —OP(═))R⁹R¹⁰, —C(═S)R⁸, —C(═S)OR⁸,        —C(═O)SR⁸, —C(═S)SR⁸, —C(═S)NR⁹R¹⁰, —C(═NR⁸)NR⁹R¹⁰, or        —NR⁸C(═NR⁸)NR⁹R¹⁰;    -   m is 1 or 2;    -   R⁴ and R⁵ are each independently H, alkyl, substituted alkyl,        haloalkyl, heteroalkyl, or substituted heteroalkyl;    -   L² is alkylene or heteroalkylene;    -   Z is H, halogen, alkyl, substituted alkyl, haloalkyl,        heteroalkyl, substituted heteroalkyl, cyano, azido, —C(O)H,        —C(O)R⁸, —S(O)R⁸, —S(O)₂R⁸, —S(O)₂NR⁸R⁹, —C(O)OR⁸, or        —C(O)NR⁹R¹⁰;    -   R² is —NR⁶R⁷; and    -   each of R⁶ and R⁷ independently is H, alkyl, substituted alkyl,        heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted        carbocyclyl, heterocyclyl, substituted heterocyclyl,        carbocylylalkyl, substituted carbocyclylalkyl,        heterocyclylalkyl, substituted heterocyclylalkyl, aryl,        substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,        substituted heteroaryl, arylalkyl, substituted arylalkyl,        heteroarylalkyl, or substituted heteroarylalkyl; or together        with the nitrogen to which they are attached form a substituted        or unsubstituted 3 to 8 membered heterocyclyl; and    -   R⁸, R⁹, and R¹⁰ are each independently H, alkyl, substituted        alkyl, haloalkyl, heteroalkyl, substituted heteroalkyl,        carbocyclyl, substituted carbocyclyl, carbocyclylalkyl,        substituted carbocyclylalkyl, heterocyclyl, substituted        heterocyclyl, heterocyclylalkyl, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, substituted        heterocyclylalkyl, arylalkyl, substituted arylalkyl,        heteroarylalkyl, substituted heteroarylalkyl,        carbocyclylalkenyl, substituted carbocyclylalkenyl,        carbocyclylalkynyl, substituted carbocyclylalkynyl,        heterocyclylalkenyl, substituted heterocyclylalkenyl,        heterocyclylalkylyl, substituted heteroalkylyl, arylalkenyl,        substituted arylalkenyl, arylalkynyl, substituted arylalkynyl,        heteroarylalkenyl, substituted heteroarylalkenyl,        heteroarylalkylyl, substituted heteroarylalkynyl,        carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl,        heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl,        arylheteroalkyl, substituted arylheteroalkyl,        heteroarylheteroalkyl, or substituted heteroarylheteroalkyl.

In another embodiment, the present invention includes a compound ofFormula Ib:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   L¹ is —NH— or —O—;    -   R¹ is H, alkyl, substituted alkyl, carbocylyl, substituted        carbocyclyl, heterocyclyl, substituted heterocyclyl,        carbocyclylalkyl, substituted carbocyclylalkyl,        heterocyclylalkyl, or substituted heterocycylalkyl;    -   X¹ is alkylene, substituted alkylene, heteroalkylene, or        substituted heteroalkylene;    -   D is aryl or heteroaryl;    -   n is 0, 1, or 2;    -   each R³ is independently alkyl, substituted alkyl, alkenyl,        substituted alkenyl, alkynyl, substituted alkynyl, halogen,        haloalkyl, haloalkoxy, heteroalkyl, substituted heteroalkyl, ═O,        —OR⁸, —SR⁸, —NR⁹R¹⁰, ═NR⁸, ═NOR⁸, ═NNR⁸R⁹, —ON, —OCN, —SCN,        —N═C═O, —NCS, —NO, —NO₂, ═N₂, —N₃, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹,        —NR⁸C(═O)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)OR⁸, —OC(═O)NR⁹R¹⁰,        —OC(═O)OR⁸, —O(═O)R⁸, —S(═O)₂OR⁸, —S(═O)₂R⁸, —OS(═O)₂OR⁸,        —S(═O)₂NR⁹R¹⁰, —S(═O)R⁸, —NR⁸S(═O)₂R⁹, —NR⁸S(═O)₂NR⁹R¹⁰,        —NR⁸S(═O)₂OR⁹, —OS(O)₂NR⁹R¹⁰, —OP(═O)(OR⁸)₂, —P(═O)(OR⁸)₂,        —P(O)(OR⁸)(R⁹), —P(O)R⁹R¹⁰, —OP(═))R⁹R¹⁰, —C(═S)R⁸, —C(═S)OR⁸,        —O(═O)SR⁸, —C(═S)SR⁸, —O(═S)NR⁹R¹⁰, —O(═NR⁸)NR⁹R¹⁰, or        —NR⁸C(═NR⁸)NR⁹R¹⁰;    -   m is 1 or 2;    -   R⁴ and R⁵ are each independently H, alkyl, substituted alkyl,        haloalkyl, heteroalkyl, or substituted heteroalkyl;    -   L² is alkylene or heteroalkylene;    -   Z is H, halogen, alkyl, substituted alkyl, haloalkyl,        heteroalkyl, substituted heteroalkyl, cyano, azido, —C(O)H,        —C(O)R⁸, —S(O)R⁸, —S(O)₂R⁸, —S(O)₂NR⁸R⁹, —C(O)OR⁸, or        —C(O)NR⁹R¹⁰;    -   R² is —NR⁶R⁷;    -   R⁶ and R⁷ together with the nitrogen to which they are attached        form a substituted or unsubstituted 3 to 8 membered        heterocyclyl; and    -   R⁸, R⁹, and R¹⁰ are each independently H, alkyl, substituted        alkyl, haloalkyl, heteroalkyl, substituted heteroalkyl,        carbocyclyl, substituted carbocyclyl, carbocyclylalkyl,        substituted carbocyclylalkyl, heterocyclyl, substituted        heterocyclyl, heterocyclylalkyl, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, substituted        heterocyclylalkyl, arylalkyl, substituted arylalkyl,        heteroarylalkyl, substituted heteroarylalkyl,        carbocyclylalkenyl, substituted carbocyclylalkenyl,        carbocyclylalkynyl, substituted carbocyclylalkynyl,        heterocyclylalkenyl, substituted heterocyclylalkenyl,        heterocyclylalkylyl, substituted heteroalkylyl, arylalkenyl,        substituted arylalkenyl, arylalkynyl, substituted arylalkynyl,        heteroarylalkenyl, substituted heteroarylalkenyl,        heteroarylalkylyl, substituted heteroarylalkynyl,        carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl,        heterocyclyl heteroalkyl, substituted heterocyclylheteroalkyl,        arylheteroalkyl, substituted arylheteroalkyl,        heteroarylheteroalkyl, or substituted heteroarylheteroalkyl.

In another embodiment, the present invention includes a compound ofFormula Ic:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   L¹ is —NH— or —O—;    -   R¹ is H, alkyl, substituted alkyl, carbocylyl, substituted        carbocyclyl, heterocyclyl, substituted heterocyclyl,        carbocyclylalkyl, substituted carbocyclylalkyl,        heterocyclylalkyl, or substituted heterocycylalkyl;    -   X¹ is alkylene, substituted alkylene, heteroalkylene, or        substituted heteroalkylene;    -   D is aryl or heteroaryl;    -   n is 0, 1, or 2;    -   each R³ is independently alkyl, substituted alkyl, alkenyl,        substituted alkenyl, alkynyl, substituted alkynyl, halogen,        haloalkyl, haloalkoxy, heteroalkyl, substituted heteroalkyl, ═O,        —OR⁸, —SR⁸, —NR⁹R¹⁰, ═NR⁸, ═NOR⁸, ═NNR⁸R⁹, —CN, —OCN, —SCN,        —N═C═O, —NCS, —NO, —NO₂, ═N₂, —N₃, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹,        —NR⁸C(═O)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)OR⁸, —OC(═O)NR⁹R¹⁰,        —OC(═O)OR⁸, —C(═O)R⁸, —S(═O)₂OR⁸, —S(═O)₂R⁸, —OS(═O)₂OR⁸,        —S(═O)₂NR⁹R¹⁰, —S(═O)R⁸, —NR⁸S(═O)₂R⁹, —NR⁸S(═O)₂NR⁹R¹⁰,        —NR⁸S(═O)₂OR⁹, —OS(O)₂NR⁹R¹⁰, —OP(═O)(OR⁸)₂, —P(═O)(OR⁸)₂,        —P(O)(OR⁸)(R⁹), —P(O)R⁹R¹⁰, —OP(═))R⁹R¹⁰, —C(═S)R⁸, —C(═S)OR⁸,        —C(═O)SR⁸, —C(═S)SR⁸, —C(═S)NR⁹R¹⁰, —C(═NR⁸)NR⁹R¹⁰, or        —NR⁸C(═NR⁸)NR⁹R¹⁰;    -   m is 1 or 2;    -   R⁴ and R⁵ are each independently H, alkyl, substituted alkyl,        haloalkyl, heteroalkyl, or substituted heteroalkyl;    -   L² is alkylene or heteroalkylene;    -   Z is H, halogen, alkyl, substituted alkyl, haloalkyl,        heteroalkyl, substituted heteroalkyl, cyano, azido, —C(O)H,        —C(O)R⁸, —S(O)R⁸, —S(O)₂R⁸, —S(O)₂NR⁸R⁹, —C(O)OR⁸, or        —C(O)NR⁹R¹⁰;    -   R² is —NR⁶R⁷; and    -   R⁶ is H, alkyl, substituted alkyl, heteroalkyl, substituted        heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl,        substituted heterocyclyl, carbocylylalkyl, substituted        carbocyclylalkyl, heterocyclylalkyl, substituted        heterocyclylalkyl, aryl, substituted aryl, arylalkyl,        substituted arylalkyl, heteroaryl, substituted heteroaryl,        arylalkyl, substituted arylalkyl, heteroarylalkyl, or        substituted heteroarylalkyl; or together with R⁷ and the        nitrogen to which they are attached form a substituted or        unsubstituted 3 to 8 membered heterocyclyl; or    -   R⁷ taken together with D, L², and the N to which both R⁷ and L²        are attached forms a substituted or unsubstituted 5 to 15        membered heterocycle or heteroaryl which may contain one or more        additional heteroatoms selected from N, O, S, or P; and    -   R⁸, R⁹, and R¹⁰ are each independently H, alkyl, substituted        alkyl, haloalkyl, heteroalkyl, substituted heteroalkyl,        carbocyclyl, substituted carbocyclyl, carbocyclylalkyl,        substituted carbocyclylalkyl, heterocyclyl, substituted        heterocyclyl, heterocyclylalkyl, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, substituted        heterocyclylalkyl, arylalkyl, substituted arylalkyl,        heteroarylalkyl, substituted heteroarylalkyl,        carbocyclylalkenyl, substituted carbocyclylalkenyl,        carbocyclylalkynyl, substituted carbocyclylalkynyl,        heterocyclylalkenyl, substituted heterocyclylalkenyl,        heterocyclylalkylyl, substituted heteroalkylyl, arylalkenyl,        substituted arylalkenyl, arylalkynyl, substituted arylalkynyl,        heteroarylalkenyl, substituted heteroarylalkenyl,        heteroarylalkylyl, substituted heteroarylalkynyl,        carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl,        heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl,        arylheteroalkyl, substituted arylheteroalkyl,        heteroarylheteroalkyl, or substituted heteroarylheteroalkyl.

In another embodiment, the present invention includes a compound ofFormula Id:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   L¹ is —NH— or —O—;    -   R¹ is H, alkyl, substituted alkyl, carbocylyl, substituted        carbocyclyl, heterocyclyl, substituted heterocyclyl,        carbocyclylalkyl, substituted carbocyclylalkyl,        heterocyclylalkyl, or substituted heterocycylalkyl;    -   X¹ is alkylene, substituted alkylene, heteroalkylene, or        substituted heteroalkylene;    -   D is aryl or heteroaryl;    -   n is 0, 1, or 2;    -   each R³ is independently alkyl, substituted alkyl, alkenyl,        substituted alkenyl, alkynyl, substituted alkynyl, halogen,        haloalkyl, haloalkoxy, heteroalkyl, substituted heteroalkyl, ═O,        —OR⁸, —SR⁸, —NR⁹R¹⁰, ═NR⁸, ═NOR⁸, ═NNR⁸R⁹, —CN, —OCN, —SCN,        —N═C═O, —NCS, —NO, —NO₂, ═N₂, —N₃, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹,        —NR⁸C(═O)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)OR⁸, —OC(═O)NR⁹R¹⁰,        —OC(═O)OR⁸, —C(═O)R⁸, —S(═O)₂OR⁸, —S(═O)₂R⁸, —OS(═O)₂OR⁸,        —S(═O)₂NR⁹R¹⁰, —S(═O)R⁸, —NR⁸S(═O)₂R⁹, NR⁸S(═O)₂NR⁹R¹⁰,        —NR⁸S(═O)₂OR⁹, —OS(O)₂NR⁹R¹⁰, —OP(═O)(OR⁸)₂, —P(═O)(OR⁸)₂,        —P(O)(OR⁸)(R⁹), —P(O)R⁹R¹⁰, —OP(═))R⁹R¹⁰, —C(═S)R⁸, —C(═S)OR⁸,        —C(═O)SR⁸, —C(═S)SR⁸, —C(═S)NR⁹R¹⁰, —C(═NR⁸)NR⁹R¹⁰, or        —NR⁸C(═NR⁸)NR⁹R¹⁰;    -   m is 1 or 2;    -   R⁴ and R⁵ are each independently H, alkyl, substituted alkyl,        haloalkyl, heteroalkyl, or substituted heteroalkyl;    -   L² is arylene-alkylene, heteroarylene-alkylene,        arylene-heteroalkylene, or heteroarylene-heteroalkylene, each of        which may be optionally substituted;    -   Z is H, halogen, alkyl, substituted alkyl, haloalkyl,        heteroalkyl, substituted heteroalkyl, cyano, azido, —C(O)H,        —C(O)R⁸, —S(O)R⁸, —S(O)₂R⁸, —S(O)₂NR⁸R⁹, —C(O)OR⁸, or        —C(O)NR⁹R¹⁰;    -   R² is —NR⁶R⁷;    -   each of R⁶ and R⁷ independently is H, alkyl, substituted alkyl,        heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted        carbocyclyl, heterocyclyl, substituted heterocyclyl,        carbocylylalkyl, substituted carbocyclylalkyl,        heterocyclylalkyl, substituted heterocyclylalkyl, aryl,        substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,        substituted heteroaryl, arylalkyl, substituted arylalkyl,        heteroarylalkyl, or substituted heteroarylalkyl; or together        with the nitrogen to which they are attached form a substituted        or unsubstituted 3 to 8 membered heterocyclyl; and    -   R⁸, R⁹, and R¹⁰ are each independently H, alkyl, substituted        alkyl, haloalkyl, heteroalkyl, substituted heteroalkyl,        carbocyclyl, substituted carbocyclyl, carbocyclylalkyl,        substituted carbocyclylalkyl, heterocyclyl, substituted        heterocyclyl, heterocyclylalkyl, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, substituted        heterocyclylalkyl, arylalkyl, substituted arylalkyl,        heteroarylalkyl, substituted heteroarylalkyl,        carbocyclylalkenyl, substituted carbocyclylalkenyl,        carbocyclylalkynyl, substituted carbocyclylalkynyl,        heterocyclylalkenyl, substituted heterocyclylalkenyl,        heterocyclylalkylyl, substituted heteroalkylyl, arylalkenyl,        substituted arylalkenyl, arylalkynyl, substituted arylalkynyl,        heteroarylalkenyl, substituted heteroarylalkenyl,        heteroarylalkylyl, substituted heteroarylalkynyl,        carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl,        heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl,        arylheteroalkyl, substituted arylheteroalkyl,        heteroarylheteroalkyl, or substituted heteroarylheteroalkyl.

In another embodiment, the present invention includes a compound ofFormula Ie:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   L¹ is —NH— or —O—;    -   R¹ is H, alkyl, substituted alkyl, carbocylyl, substituted        carbocyclyl, heterocyclyl, substituted heterocyclyl,        carbocyclylalkyl, substituted carbocyclylalkyl,        heterocyclylalkyl, or substituted heterocycylalkyl;    -   X¹ is alkylene, substituted alkylene, heteroalkylene, or        substituted heteroalkylene;    -   D is aryl or heteroaryl;    -   n is 0, 1, or 2;    -   each R³ is independently alkyl, substituted alkyl, alkenyl,        substituted alkenyl, alkynyl, substituted alkynyl, halogen,        haloalkyl, haloalkoxy, heteroalkyl, substituted heteroalkyl, ═O,        —OR⁸, —SR⁸, —NR⁹R¹⁰, ═NR⁸, ═NOR⁸, ═NNR⁸R⁹, —CN, —OCN, —SCN,        —N═C═O, —NCS, —NO, —NO₂, ═N₂, —N₃, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹,        —NR⁸C(═O)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)OR⁸, —OC(═O)NR⁹R¹⁰,        —OC(═O)OR⁸, —C(═O)R⁸, —S(═O)₂OR⁸, —S(═O)₂R⁸, —OS(═O)₂OR⁸,        —S(═O)₂NR⁹R¹⁰, —S(═O)R⁸, —NR⁸S(═O)₂R⁹, —NR⁸S(═O)₂NR⁹R¹⁰,        —NR⁸S(═O)₂OR⁹, —OS(O)₂NR⁹R¹⁰, —OP(═O)(OR⁸)₂, —P(═O)(OR⁸)₂,        —P(O)(OR⁸)(R⁹), —P(O)R⁹R¹⁰, —OP(═))R⁹R¹⁰, —C(═S)R⁸, —C(═S)OR⁸,        —C(═O)SR⁸, —C(═S)SR⁸, —C(═S)NR⁹R¹⁰, —C(═NR⁸)NR⁹R¹⁰, or        —NR⁸C(═NR⁸)NR⁹R¹⁰;    -   m is 1 or 2;    -   L² is alkylene or heteroalkylene;    -   Z is H, halogen, alkyl, substituted alkyl, haloalkyl,        heteroalkyl, substituted heteroalkyl, cyano, azido, —C(O)H,        —C(O)R⁸, —S(O)R⁸, —S(O)₂R⁸, —S(O)₂NR⁸R⁹, —C(O)OR⁸, or        —C(O)NR⁹R¹⁰;    -   R² is —NR⁶R⁷;    -   each of R⁶ and R⁷ independently is H, alkyl, substituted alkyl,        heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted        carbocyclyl, heterocyclyl, substituted heterocyclyl,        carbocylylalkyl, substituted carbocyclylalkyl,        heterocyclylalkyl, substituted heterocyclylalkyl, aryl,        substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,        substituted heteroaryl, arylalkyl, substituted arylalkyl,        heteroarylalkyl, or substituted heteroarylalkyl; or together        with the nitrogen to which they are attached form a substituted        or unsubstituted 3 to 8 membered heterocyclyl;    -   R⁴ and R⁵ taken together with the carbon to which they are        attached form a —C(═O); and    -   R⁸, R⁹, and R¹⁰ are each independently H, alkyl, substituted        alkyl, haloalkyl, heteroalkyl, substituted heteroalkyl,        carbocyclyl, substituted carbocyclyl, carbocyclylalkyl,        substituted carbocyclylalkyl, heterocyclyl, substituted        heterocyclyl, heterocyclylalkyl, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, substituted        heterocyclylalkyl, arylalkyl, substituted arylalkyl,        heteroarylalkyl, substituted heteroarylalkyl,        carbocyclylalkenyl, substituted carbocyclylalkenyl,        carbocyclylalkynyl, substituted carbocyclylalkynyl,        heterocyclylalkenyl, substituted heterocyclylalkenyl,        heterocyclylalkylyl, substituted heteroalkylyl, arylalkenyl,        substituted arylalkenyl, arylalkynyl, substituted arylalkynyl,        heteroarylalkenyl, substituted heteroarylalkenyl,        heteroarylalkylyl, substituted heteroarylalkynyl,        carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl,        heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl,        arylheteroalkyl, substituted arylheteroalkyl,        heteroarylheteroalkyl, or substituted heteroarylheteroalkyl.

In one embodiment, which may be combined with other aspects andembodiments, L¹ is oxygen.

In another embodiment, which may be combined with other aspects andembodiments, X¹ is alkylene.

In another embodiment, which may be combined with other aspects andembodiments, D is aryl. In a further embodiment, D is phenyl.

In another embodiment, which may be combined with other aspects andembodiments, L² is alkylene;

Another aspect of the present invention includes a compound of thepresent invention and one or more pharmaceutically acceptable carrier orexcipient. In a further embodiment, the composition further comprisesone or more additional therapeutic agent.

Another aspect of the present invention includes a compound of thepresent invention in a method for treating a viral infection. In oneembodiment, the treatment results in one or more of a reduction in viralload or clearance of viral RNA.

Another aspect of the present invention includes a compound of thepresent invention for use in the manufacture of a medicament for thetreatment of a viral infection.

Another aspect of the present invention includes a compound of thepresent invention for the use in treating a viral infection.

In one embodiment, either such use or compound for treatment results inone or more of a reduction in viral load or clearance of RNA.

Another aspect of the present invention includes a compound of thepresent invention in a method for treating or preventing melanoma,non-small cell lung carcinoma, hepatocellular carcinoma, basal cellcarcinoma, renal cell carcinoma, myeloma, allergic rhinitis, asthma,COPD, ulcerative colitis, hepatic fibrosis, HBV, HCV, HPV, RSV, SARS,HIV, or influenza.

Another aspect of the present invention includes a compound of thepresent invention for use in the manufacture of a medicament for thetreatment or prevention of melanoma, non-small cell lung carcinoma,hepatocellular carcinoma, basal cell carcinoma, renal cell carcinoma,myeloma, allergic rhinitis, asthma, COPD, ulcerative colitis, hepaticfibrosis, HBV, HCV, HPV, RSV, SARS, HIV, or influenza.

While not wishing to be bound by theory, the inventors currently believethat the compounds of Formula I are agonists of TLR-7 and may also beagonists of other TLRs.

As noted an aspect of the present invention includes a pharmaceuticalcomposition comprising a compound of the present invention and one ormore pharmaceutically acceptable carrier or excipient. Thepharmaceutical composition of the present invention may further compriseone or more additional therapeutic agent. The one or more additionaltherapeutic agent may be, without limitation, selected from:interferons, ribavirin or its analogs, HCV NS3 protease inhibitors,alpha-glucosidase 1 inhibitors, hepatoprotectants, nucleoside ornucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitorsof HCV NS5B polymerase, HCV NS5A inhibitors, HCV NS4A inhibitors, HCVNS4B inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRESinhibitors, pharmacokinetic enhancers, and other drugs for treating HCV,or mixtures thereof.

As noted, an aspect of the present invention includes a method fortreating a viral infection comprising administering a compound of thepresent invention. The compound is administered to a human subject inneed thereof, such as a human being who is infected with a virus of theFlaviviridae family, such as hepatitis C virus. In one embodiment, theviral infection is acute or chronic HCV infection. In one embodiment,the treatment results in one or more of a reduction in viral load orclearance of RNA. As noted hereinabove, there are a number of diseases,disorders, and conditions linked to TLRs such that therapies using a TLRagonist are believed promising, including but not limited to melanoma,non-small cell lung carcinoma, hepatocellular carcinoma, basal cellcarcinoma, renal cell carcinoma, myeloma, allergic rhinitis, asthma,COPD, ulcerative colitis, hepatic fibrosis, and viral infections such asHBV, HCV, HPV, RSV, SARS, HIV, or influenza

As noted, an aspect of the present invention includes the use of acompound according to the present invention for the manufacture of amedicament for the treatment of a viral infection. Another aspect of thepresent invention includes a compound according to the present inventionfor the use in treating a viral infection. In one embodiment, the viralinfection is acute or chronic HCV infection. In one embodiment, thetreatment results in one or more of a reduction in viral load orclearance of RNA. In one embodiment, the viral infection is acute orchronic HBV infection. In one embodiment, the treatment results in oneor more of a reduction in viral load or clearance of RNA.

The present invention includes combinations of aspects and embodiments,as well as preferences, as herein described throughout the presentspecification.

DETAILED DESCRIPTION

Reference will now be made in detail to certain claims of the invention,examples of which are illustrated in the accompanying structures andformulas. While the invention will be described in conjunction with theenumerated claims, it will be understood that they are not intended tolimit the invention to those claims. On the contrary, the invention isintended to cover all alternatives, modifications, and equivalents,which may be included within the scope of the present invention asdefined by the claims.

All documents referenced herein are each incorporated by reference intheir entirety for all purposes.

Definitions

Unless stated otherwise, the following terms and phrases as used hereinare intended to have the following meanings. The fact that a particularterm or phrase is not specifically defined should not be correlated toindefiniteness or lacking clarity, but rather terms herein are usedwithin their ordinary meaning. When trade names are used herein,applicants intend to independently include the tradename product and theactive pharmaceutical ingredient(s) of the tradename product.

The term “treating”, and grammatical equivalents thereof, when used inthe context of treating a disease, means slowing or stopping theprogression of a disease, or ameliorating at least one symptom of adisease, more preferably ameliorating more than one symptom of adisease. For example, treatment of a hepatitis C virus infection caninclude reducing the HCV viral load in an HCV infected human being,and/or reducing the severity of jaundice present in an HCV infectedhuman being.

As used herein, “a compound of the invention” or “a compound of formulaI or formula Ia” means a compound of formula I or Ia, includingalternative forms thereof such as, solvated forms, hydrated forms,esterified forms, or physiologically functional derivatives thereof.Compounds of the invention also include tautomeric forms thereof, e.g.,tautomeric “enols” as described herein. Similarly, with respect toisolatable intermediates, the phrase “a compound of formula (number)”means a compound of that formula and alternative forms thereof.

“Alkyl” is hydrocarbon containing normal, secondary, tertiary or cycliccarbon atoms. For example, an alkyl group can have 1 to 20 carbon atoms(i.e, C₁-C₂₀ alkyl), 1 to 10 carbon atoms (i.e., C₁-C₁₀ alkyl), or 1 to6 carbon atoms (i.e., C₁-C₆ alkyl). Examples of suitable alkyl groupsinclude, but are not limited to, methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃),1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl,—CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl(i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, and octyl (—(CH₂)₇CH₃).

“Alkoxy” means a group having the formula —O-alkyl, in which an alkylgroup, as defined above, is attached to the parent molecule via anoxygen atom. The alkyl portion of an alkoxy group can have 1 to 20carbon atoms (i.e., C₁-C₂₀ alkoxy), 1 to 12 carbon atoms (i.e., C₁-C₁₂alkoxy), or 1 to 6 carbon atoms (i.e., C₆ alkoxy). Examples of suitablealkoxy groups include, but are not limited to, methoxy (—O—CH₃ or —OMe),ethoxy (—OCH₂CH₃ or —OEt), t-butoxy (—O—C(CH₃)₃ or —OtBu), and the like.

“Haloalkyl” is an alkyl group, as defined above, in which one or morehydrogen atoms of the alkyl group is replaced with a halogen atom. Thealkyl portion of a haloalkyl group can have 1 to 20 carbon atoms (i.e.,C₁-C₂₀ haloalkyl), 1 to 12 carbon atoms(i.e., C₁-C₁₂ haloalkyl), or 1 to6 carbon atoms (i.e., C₁-C₆ alkyl). Examples of suitable haloalkylgroups include, but are not limited to, —CF₃, —CHF₂, —CFH₂, —CH₂CF₃, andthe like.

“Alkenyl” is a hydrocarbon containing normal, secondary, tertiary, orcyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp2 double bond. For example, an alkenyl group can have 2to 20 carbon atoms (i.e., C₂-C₂₀ alkenyl), 2 to 12 carbon atoms (i.e.,C₂-C₁₂ alkenyl), or 2 to 6 carbon atoms (i.e., C₂-C₆ alkenyl). Examplesof suitable alkenyl groups include, but are not limited to, vinyl(—CH═CH₂), allyl (—CH₂CH═CH₂), cyclopentenyl (—C₅H₇), and 5-hexenyl(—CH₂CH₂CH₂CH₂CH═CH₂).

“Alkynyl” is a hydrocarbon containing normal, secondary, tertiary orcyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp triple bond. For example, an alkynyl group can have 2to 20 carbon atoms (i.e., C₂-C₂₀ alkynyl), 2 to 12 carbon atoms (i.e.,C₂-C₁₂ alkyne), or 2 to 6 carbon atoms (i.e., C₂-C₆ alkynyl). Examplesof suitable alkynyl groups include, but are not limited to, acetylenic(—C≡CH), propargyl (—CH₂C≡CH), and the like.

“Alkylene” refers to a saturated, branched or straight chain or cyclichydrocarbon radical having two monovalent radical centers derived by theremoval of two hydrogen atoms from the same or two different carbonatoms of a parent alkane. For example, an alkylene group can have 1 to20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typicalalkylene radicals include, but are not limited to, methylene (—CH₂—),1,1-ethylene (—CH(CH₃)—), 1,2-ethylene (—CH₂CH₂—), 1,1-propylene(—CH(CH₂CH₃)—), 1,2-propylene (—CH₂CH(CH₃)—), 1,3-propylene(—CH₂CH₂CH₂—), 1,4-butylene (—CH₂CH₂CH₂CH₂—), and the like.

“Alkenylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical having two monovalent radical centers derivedby the removal of two hydrogen atoms from the same or two differentcarbon atoms of a parent alkene. For example, and alkenylene group canhave 2 to 20 carbon atoms, 2 to 10 carbon atoms, or 2 to 6 carbon atoms.Typical alkenylene radicals include, but are not limited to,1,2-ethylene (—CH═CH—).

“Alkynylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical having two monovalent radical centers derivedby the removal of two hydrogen atoms from the same or two differentcarbon atoms of a parent alkyne. For example, an alkynylene group canhave 2 to 20 carbon atoms, 2 to 10 carbon atoms, or 2 to 6 carbon atoms.Typical alkynylene radicals include, but are not limited to, acetylene(—C≡C—), propargyl (—CH₂C≡C—), and 4-pentynyl (—CH₂CH₂CH₂C≡C—).

“Aminoalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, is replaced with an amino radical.

“Amidoalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, is replaced with a —NR^(a)COR^(b) group where R^(a) ishydrogen or alkyl and R^(b) is alkyl, substituted alkyl, aryl, orsubstituted aryl as defined herein, e.g., —(CH₂)₂—NHC(O)CH₃,—(CH₂)₃—NH—C(O)—CH₃, and the like.

“Aryl” means a monovalent aromatic hydrocarbon radical derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. For example, an aryl group can have 6 to 20 carbonatoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Typical arylgroups include, but are not limited to, radicals derived from benzene(e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl,and the like.

“Arylene” refers to an aryl as defined above having two monovalentradical centers derived by the removal of two hydrogen atoms from thesame or two different carbon atoms of a parent aryl. Typical aryleneradicals include, but are not limited to, phenylene.

“Arylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, is replaced with an aryl radical. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. The arylalkyl group can comprise6 to 20 carbon atoms, e.g., the alkyl moiety is 1 to 6 carbon atoms andthe aryl moiety is 6 to 14 carbon atoms.

“Arylalkenyl” refers to an acyclic alkenyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, but also an sp2 carbon atom, is replaced with an arylradical. The aryl portion of the arylalkenyl can include, for example,any of the aryl groups disclosed herein, and the alkenyl portion of thearylalkenyl can include, for example, any of the alkenyl groupsdisclosed herein. The arylalkenyl group can comprise 8 to 20 carbonatoms, e.g., the alkenyl moiety is 2 to 6 carbon atoms and the arylmoiety is 6 to 14 carbon atoms.

“Arylalkynyl” refers to an acyclic alkynyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, but also an sp carbon atom, is replaced with an arylradical. The aryl portion of the arylalkynyl can include, for example,any of the aryl groups disclosed herein, and the alkynyl portion of thearylalkynyl can include, for example, any of the alkynyl groupsdisclosed herein. The arylalkynyl group can comprise 8 to 20 carbonatoms, e.g., the alkynyl moiety is 2 to 6 carbon atoms and the arylmoiety is 6 to 14 carbon atoms.

“Halogen” refers to F, Cl, Br, or I.

As used herein, the term “haloalkoxy” refers to a group —OR^(a), whereR^(a) is a haloalkyl group as herein defined. As non-limiting examples,haloalkoxy groups include —O(CH₂)F, —O(CH)F₂, and —OCF₃.

“Heteroalkyl” refers to an alkyl group where one or more carbon atomshave been replaced with a heteroatom, such as, O, N, or S. For example,if the carbon atom of the alkyl group which is attached to the parentmolecule is replaced with a heteroatom (e.g., O, N, P, or S) theresulting heteroalkyl groups are, respectively, an alkoxy group (e.g.,—OCH₃, etc.), an amine (e.g., —NHCH₃, —N(CH₃)₂, and the like), or athioalkyl group (e.g., —SCH₃). If a non-terminal carbon atom of thealkyl group which is not attached to the parent molecule is replacedwith a heteroatom (e.g., O, N, P, or S) and the resulting heteroalkylgroups are, respectively, an alkyl ether (e.g., —CH₂CH₂—O—CH₃, etc.), analkyl amine (e.g., —CH₂NHCH₃, —CH₂N(CH₃)₂, and the like), or a thioalkylether (e.g., —CH₂—S—CH₃). If a terminal carbon atom of the alkyl groupis replaced with a heteroatom (e.g., O, N, or S), the resultingheteroalkyl groups are, respectively, a hydroxyalkyl group (e.g.,—CH₂CH₂—OH), an aminoalkyl group (e.g., —CH₂NH₂), or an alkyl thiolgroup (e.g., —CH₂CH₂—SH). A heteroalkyl group can have, for example, 1to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. AC₁-C₆ heteroalkyl group means a heteroalkyl group having 1 to 6 carbonatoms.

“Heterocycle” or “heterocyclyl” refers to a saturated or partiallysaturated cyclic group having from 1 to 14 carbon atoms and from 1 to 6heteroatoms selected from N, S, P, or O, and includes single ring andmultiple ring systems including, fused, bridged, and Spiro ring systems.“Heterocycle” or “heterocyclyl” as used herein includes by way ofexample and not limitation those heterocycles described in Paquette, LeoA.; Principles of Modern Heterocyclic Chemistry (W. A. Benjamin, NewYork, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistryof Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons,New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and28; and J. Am. Chem. Soc. (1960) 82:5566. In one embodiment, the carbon,nitrogen, phosphorous, or sulfur atom(s) of the heterocyclic group maybe oxidized to provide for C(═O), N-oxide, phosphinane oxide, sulfinyl,or sulfonyl moieties.

As one example, substituted heterocyclyls include, for example,heterocyclic rings substituted with any of the substituents disclosedherein including oxo groups. A non-limiting example of a carbonylsubstituted heterocyclyl is:

Examples of heterocycles include by way of example and not limitationdihydroypyridyl, tetrahydropyridyl(piperidyl), tetrahydrothiophenyl,sulfur oxidized tetrahydrothiophenyl, piperidinyl, 4-piperidonyl,pyrrolidinyl, azetidinyl, 2-pyrrolidonyl, tetrahydrofuranyl,decahydroquinolinyl, octahydroisoquinolinyl, pyranyl, morpholinyl, andbis-tetrahydrofuranyl:

“Heterocyclylene” refers to a heterocyclyl, as defined herein, derivedby replacing a hydrogen atom from a carbon atom or heteroatom of aheterocyclyl, with an open valence. Similarly, “heteroarylene” refers toan aromatic heterocyclylene.

“Heterocyclylalkyl” refers to an acyclic alkyl radical in which one ofthe hydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, is replaced with a heterocyclyl radical (i.e., aheterocyclyl-alkylene-moiety). Typical heterocyclyl alkyl groupsinclude, but are not limited to heterocyclyl-CH₂—,2-(heterocyclyl)ethan-1-yl, and the like, wherein the “heterocyclyl”portion includes any of the heterocyclyl groups described above,including those described in Principles of Modern HeterocyclicChemistry. One skilled in the art will also understand that theheterocyclyl group can be attached to the alkyl portion of theheterocyclyl alkyl by means of a carbon-carbon bond or acarbon-heteroatom bond, with the proviso that the resulting group ischemically stable. The heterocyclylalkyl group comprises 2 to 20 carbonatoms and 1-6 heteroatoms, e.g., the alkyl portion of theheterocyclylalkyl group comprises 1 to 6 carbon atoms and theheterocyclyl moiety comprises 1 to 14 carbon atoms. Examples ofheterocyclylalkyls include by way of example and not limitation5-membered sulfur, oxygen, phosphorus, and/or nitrogen containingheterocycles such as pyrrolidiylmethyl, 2-tetrahydrofuranylylethan-1-yl,and the like, 6-membered sulfur, oxygen, and/or nitrogen containingheterocycles such as piperidinylmethyl, morpholinylmethyl,piperidinylethyl, teterahydropyranylethyl, and the like.

“Heterocyclylalkenyl” refers to an acyclic alkenyl radical in which oneof the hydrogen atoms bonded to a carbon atom, typically a terminal orsp3 carbon atom, but also a sp2 carbon atom, is replaced with aheterocyclyl radical (i.e., a heterocyclyl-alkenylene-moiety). Theheterocyclyl portion of the heterocyclyl alkenyl group includes any ofthe heterocyclyl groups described herein, including those described inPrinciples of Modern Heterocyclic Chemistry, and the alkenyl portion ofthe heterocyclyl alkenyl group includes any of the alkenyl groupsdisclosed herein. One skilled in the art will also understand that theheterocyclyl group can be attached to the alkenyl portion of theheterocyclyl alkenyl by means of a carbon-carbon bond or acarbon-heteroatom bond, with the proviso that the resulting group ischemically stable. The heterocyclyl alkenyl group comprises 2 to 20carbon atoms, e.g., the alkenyl portion of the heterocyclyl alkenylgroup comprises 2 to 6 carbon atoms and the heterocyclyl moietycomprises 1 to 14 carbon atoms.

“Heterocyclylalkynyl” refers to an acyclic alkynyl radical in which oneof the hydrogen atoms bonded to a carbon atom, typically a terminal orsp3 carbon atom, but also an sp carbon atom, is replaced with aheterocyclyl radical (i.e., a heterocyclyl-alkynylene-moiety). Theheterocyclyl portion of the heterocyclyl alkynyl group includes any ofthe heterocyclyl groups described herein, including those described inPrinciples of Modern Heterocyclic Chemistry, and the alkynyl portion ofthe heterocyclyl alkynyl group includes any of the alkynyl groupsdisclosed herein. One skilled in the art will also understand that theheterocyclyl group can be attached to the alkynyl portion of theheterocyclyl alkynyl by means of a carbon-carbon bond or acarbon-heteroatom bond, with the proviso that the resulting group ischemically stable. The heterocyclyl alkynyl group comprises 3 to 20carbon atoms, e.g., the alkynyl portion of the heterocyclyl alkynylgroup comprises 2 to 6 carbon atoms and the heterocyclyl moietycomprises 1 to 14 carbon atoms.

“Heteroaryl” refers to a monovalent aromatic heterocyclyl having atleast one heteroatom in the ring. Thus, “heteroaryl” refers to anaromatic group of from 1 to 14 carbon atoms and 1 to 6 heteroatomsselected from oxygen, nitrogen, sulfur, or phosphorous. For multiplering systems, by way of example, the term “heteroaryl” includes fused,bridged, and spiro ring systems having aromatic and non-aromatic rings.In one embodiment, the carbon, nitrogen, sulfur or phosphorus ringatom(s) of the heteroaryl group may be oxidized to provide for C(═O),N-oxide, sulfinyl, or sulfonyl moieties.

Examples of heteroaryls include by way of example and not limitationpyridyl, thiazolyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl,quinolinyl, isoquinolinyl, benzimidazolyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl,thienyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl,phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl,pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl,pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl,acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl,imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl,isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl,benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl.

“Carbocycle” or “carbocyclyl” refers to a saturated, partiallyunsaturated or aromatic ring having 3 to 7 carbon atoms as a monocycle,7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as apolycycle. Monocyclic carbocycles have 3 to 6 ring atoms, still moretypically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ringatoms, e.g., arranged as a bicyclo (4,5), (5,5), (5,6) or (6,6) system,or 9 or 10 ring atoms arranged as a bicyclo (5,6) or (6,6) system.Carbocycles include non-aromatic mono-, bi-, and poly-cyclic rings,whether fused, bridged, or spiro. Non-limiting examples of monocycliccarbocycles include cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, and the like.

“Carbocyclylene” refers to a carbocyclyl or carbocycle as defined abovehaving two monovalent radical centers derived by the removal of twohydrogen atoms from the same or two different carbon atoms of a parentcarbocyclyl. Typical carbocyclylene radicals include, but are notlimited to, phenylene.

“Arylheteroalkyl” refers to a heteroalkyl as defined herein, in which ahydrogen atom, which may be attached either to a carbon atom or aheteroatom, has been replaced with an aryl group as defined herein. Thearyl groups may be bonded to a carbon atom of the heteroalkyl group, orto a heteroatom of the heteroalkyl group, provided that the resultingarylheteroalkyl group provides a chemically stable moiety. For example,an arylheteroalkyl group can have the general formulae -alkylene-O-aryl,-alkylene-O-alkylene-aryl, -alkylene-NH-aryl,-alkylene-NH-alkylene-aryl, -alkylene-S-aryl, -alkylene-S-alkylene-aryl,and the like. In addition, any of the alkylene moieties in the generalformulae above can be further substituted with any of the substituentsdefined or exemplified herein.

“Heteroarylalkyl” refers to an alkyl group, as defined herein, in whicha hydrogen atom has been replaced with a heteroaryl group as definedherein. Non-limiting examples of heteroaryl alkyl include—CH₂-pyridinyl, —CH₂-pyrrolyl, —CH₂-oxazolyl, —CH₂-indolyl,—CH₂-isoindolyl, —CH₂-purinyl, —CH₂-furanyl, —CH₂-thienyl,—CH₂-benzofuranyl, —CH₂-benzothiophenyl, —CH₂-carbazolyl,—CH₂-imidazolyl, —CH₂-thiazolyl, —CH₂-isoxazolyl, —CH₂-pyrazolyl,—CH₂-isothiazolyl, —CH₂-quinolyl, —CH₂-isoquinolyl, —CH₂-pyridazyl,—CH₂-pyrimidyl, —CH₂-pyrazyl, —CH(CH₃)-pyridinyl, —CH(CH₃)-pyrrolyl,—CH(CH₃)-oxazolyl, —CH(CH₃)-indolyl, —CH(CH₃)-isoindolyl,—CH(CH₃)-purinyl, —CH(CH₃)-furanyl, —CH(CH₃)-thienyl,—CH(CH₃)-benzofuranyl, —CH(CH₃)-benzothiophenyl, —CH(CH₃)-carbazolyl,—CH(CH₃)-imidazolyl, —CH(CH₃)-thiazolyl, —CH(CH₃)-isoxazolyl,—CH(CH₃)-pyrazolyl, —CH(CH₃)-isothiazolyl, —CH(CH₃)-quinolyl,—CH(CH₃)-isoquinolyl, —CH(CH₃)-pyridazyl, —CH(CH₃)-pyrimidyl,—CH(CH₃)-pyrazyl, and the like.

The term “optionally substituted” in reference to a particular moiety ofthe compound of the Formulae of the invention, for example an optionallysubstituted aryl group, refers to a moiety having 0, 1, or moresubstituents.

The term “substituted” in reference to alkyl, aryl, arylalkyl,carbocyclyl, heterocyclyl, and other groups used herein, for example,“substituted alkyl”, “substituted aryl”, “substituted arylalkyl”,“substituted heterocyclyl”, and “substituted carbocyclyl” means a group,alkyl, alkylene, aryl, arylalkyl, heterocyclyl, carbocyclylrespectively, in which one or more hydrogen atoms are each independentlyreplaced with a non-hydrogen substituent. Typical substituents include,but are not limited to, —X, —R, —O—, ═O, —OR, —SR, —S—, —NR₂, —N(+)R₃,═NR, ═NOR, ═NNR₂, —CX₃, —CRX₂, —CR₂X, —CN, —OCN, —SCN, —N═C═O, —NCS,—NO, —NO₂, ═N₂, —N₃, —NRC(═O)R, —NRC(═O)OR, —NRC(═O)NRR, —C(═O)NRR,—C(═O)OR, —OC(═O)NRR, —OC(═O)OR, —C(═O)R, —S(═O)₂OR, —S(═O)₂R,—OS(═O)₂OR, —S(═O)₂NRR, —S(═O)R, —NRS(═O)₂R, —NRS(═O)₂NRR, —NRS(═O)₂OR,—OP(═O)(OR)₂, —P(═O)(OR)₂, —P(O)(OR)(R), —OP(═O)R₂, —P(═O)R₂, —C(═S)R,—C(═S)OR, —C(═O)SR, —C(═S)SR, —C(═S)NRR, —C(═NR)NRR, —NRC(═NR)NRR, whereeach X is independently a halogen: F, Cl, Br, or I; and each R isindependently H, alkyl, aryl, arylalkyl, a heterocycle, or a protectinggroup or prodrug moiety. Divalent groups may also be similarlysubstituted.

Those skilled in the art will recognize that when moieties such as“alkyl”, “aryl”, “heterocyclyl”, etc. are substituted with one or moresubstituents, they could alternatively be referred to as “alkylene”,“arylene”, “heterocyclylene”, etc. moieties (i.e., indicating that atleast one of the hydrogen atoms of the parent “alkyl”, “aryl”,“heterocyclyl” moieties has been replaced with the indicatedsubstituent(s)). When moieties such as “alkyl”, “aryl”, “heterocyclyl”,etc. are referred to herein as “substituted” or are showndiagrammatically to be substituted (or optionally substituted, e.g.,when the number of substituents ranges from zero to a positive integer),then the terms “alkyl”, “aryl”, “heterocyclyl”, etc. are understood tobe interchangeable with “alkylene”, “arylene”, “heterocyclylene”, etc.

Further, those skilled in the art will recognize that when terms hereindefined are used in combination, the resulting combined term is usedaccording to the definition. For example, although a term such as“carbocyclylheteroalkyl” may not carry a specific definition hereinshould not be equated to a lack of clarity. Rather, such a term is usedwithin the accepted meaning in the art to describe a carbocyclyl grouplinked via a heteroalkyl group. Other such terms are used consistently.

As will be appreciated by those skilled in the art, the compounds of thepresent invention are capable of existing in solvated or hydrated form.The scope of the present invention includes such forms. Again, as willbe appreciated by those skilled in the art, the compounds may be capableof esterification. The scope of the present invention includes estersand other physiologically functional derivatives. The scope of thepresent invention also includes tautomeric forms, namely, tautomeric“enols” as herein described. In addition, the scope of the presentinvention includes prodrug forms of the compound herein described.

The term “prodrug” as used herein refers to any compound that whenadministered to a biological system generates the drug substance, i.e.,active ingredient, as a result of spontaneous chemical reaction(s),enzyme catalyzed chemical reaction(s), photolysis, and/or metabolicchemical reaction(s). A prodrug is thus a covalently modified analog orlatent form of a therapeutically active compound.

One skilled in the art will recognize that substituents and othermoieties of the compounds of the invention should be selected in orderto provide a compound which is sufficiently stable to provide apharmaceutically useful compound which can be formulated into anacceptably stable pharmaceutical composition. Compounds of the inventionwhich have such stability are contemplated as falling within the scopeof the present invention.

As will be appreciated by those skilled in the art, the compounds of thepresent invention may contain one or more chiral centers. The scope ofthe present invention includes such forms. Again, as will be appreciatedby those skilled in the art, the compound is capable of esterificationor hydrolysis. The scope of the present invention includes esters andother physiologically functional derivatives. The scope of the presentinvention also includes tautomeric forms, namely, tautomeric “enols” asherein described. In addition, the scope of the present inventionincludes prodrug forms of the compound herein described. The compoundsof the present invention may crystallize in more than one form, acharacteristic known as polymorphism, and such polymorphic forms(“polymorphs”) are within the scope of the present invention.Polymorphism generally can occur as a response to changes intemperature, pressure, or both. Polymorphism can also result fromvariations in the crystallization process. Polymorphs can bedistinguished by various physical characteristics known in the art suchas x-ray diffraction patterns, solubility, and melting point.

Certain of the compounds described herein contain one or more chiralcenters, or may otherwise be capable of existing as multiplestereoisomers. The scope of the present invention includes mixtures ofstereoisomers as well as purified enantiomers orenantiomerically/diastereomerically enriched mixtures. Also includedwithin the scope of the invention are the individual isomers of thecompounds represented by the formulae of the present invention, as wellas any wholly or partially equilibrated mixtures thereof. The presentinvention also includes the individual isomers of the compoundsrepresented by the formulas above as mixtures with isomers thereof inwhich one or more chiral centers are inverted.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g., melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork. Many organic compounds exist in optically active forms, i.e., theyhave the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes D and L or R and Sare used to denote the absolute configuration of the molecule about itschiral center(s). The prefixes d and l or (+) and (−) are employed todesignate the sign of rotation of plane-polarized light by the compound,with (−) or 1 meaning that the compound is levorotatory. A compoundprefixed with (+) or d is dextrorotatory. For a given chemicalstructure, these stereoisomers are identical except that they are mirrorimages of one another. A specific stereoisomer may also be referred toas an enantiomer, and a mixture of such isomers is often called anenantiomeric mixture. A 50:50 mixture of enantiomers is referred to as aracemic mixture or a racemate, which may occur where there has been nostereoselection or stereospecificity in a chemical reaction or process.The terms “racemic mixture” and “racemate” refer to an equimolar mixtureof two enantiomeric species, devoid of optical activity.

The present invention includes a salt or solvate of the compounds hereindescribed, including combinations thereof such as a solvate of a salt.The compounds of the present invention may exist in solvated, forexample hydrated, as well as unsolvated forms, and the present inventionencompasses all such forms.

Typically, but not absolutely, the salts of the present invention arepharmaceutically acceptable salts. Salts encompassed within the term“pharmaceutically acceptable salts” refer to non-toxic salts of thecompounds of this invention.

Examples of suitable pharmaceutically acceptable salts include inorganicacid addition salts such as chloride, bromide, sulfate, phosphate, andnitrate; organic acid addition salts such as acetate, galactarate,propionate, succinate, lactate, glycolate, malate, tartrate, citrate,maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate;salts with acidic amino acid such as aspartate and glutamate; alkalimetal salts such as sodium salt and potassium salt; alkaline earth metalsalts such as magnesium salt and calcium salt; ammonium salt; organicbasic salts such as trimethylamine salt, triethylamine salt, pyridinesalt, picoline salt, dicyclohexylamine salt, andN,N′-dibenzylethylenediamine salt; and salts with basic amino acid suchas lysine salt and arginine salt. The salts may be in some caseshydrates or ethanol solvates.

Protecting Groups

In the context of the present invention, protecting groups includeprodrug moieties and chemical protecting groups.

Protecting groups are available, commonly known and used, and areoptionally used to prevent side reactions with the protected groupduring synthetic procedures, i.e. routes or methods to prepare thecompounds of the invention. For the most part the decision as to whichgroups to protect, when to do so, and the nature of the chemicalprotecting group “PG” will be dependent upon the chemistry of thereaction to be protected against (e.g., acidic, basic, oxidative,reductive or other conditions) and the intended direction of thesynthesis. The PG groups do not need to be, and generally are not, thesame if the compound is substituted with multiple PG. In general, PGwill be used to protect functional groups such as carboxyl, hydroxyl,thio, or amino groups and to thus prevent side reactions or to otherwisefacilitate the synthetic efficiency. The order of deprotection to yieldfree, deprotected groups is dependent upon the intended direction of thesynthesis and the reaction conditions to be encountered, and may occurin any order as determined by the artisan.

Various functional groups of the compounds of the invention may beprotected. For example, protecting groups for —OH groups (whetherhydroxyl, carboxylic acid, phosphonic acid, or other functions) include“ether- or ester-forming groups”. Ether- or ester-forming groups arecapable of functioning as chemical protecting groups in the syntheticschemes set forth herein. However, some hydroxyl and thio protectinggroups are neither ether- nor ester-forming groups, as will beunderstood by those skilled in the art, and are included with amides,discussed below.

A very large number of hydroxyl protecting groups and amide-forminggroups and corresponding chemical cleavage reactions are described inProtective Groups in Organic Synthesis, Theodora W. Greene and Peter G.M. Wuts (John Wiley & Sons, Inc., New York, 1999, ISBN 0-471-16019-9)(“Greene”). See also Kocienski, Philip J.; Protecting Groups (GeorgThieme Verlag Stuttgart, New York, 1994), which is incorporated byreference in its entirety herein. In particular Chapter 1, ProtectingGroups: An Overview, pages 1-20, Chapter 2, Hydroxyl Protecting Groups,pages 21-94, Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4,Carboxyl Protecting Groups, pages 118-154, Chapter 5, CarbonylProtecting Groups, pages 155-184. For protecting groups for carboxylicacid, phosphonic acid, phosphonate, sulfonic acid and other protectinggroups for acids see Greene as set forth below. Such groups include byway of example and not limitation, esters, amides, hydrazides, and thelike.

Ether- and Ester-Forming Protecting Groups

Ester-forming groups include: (1) phosphonate ester-forming groups, suchas phosphonamidate esters, phosphorothioate esters, phosphonate esters,and phosphon-bis-amidates; (2) carboxyl ester-forming groups, and (3)sulphur ester-forming groups, such as sulphonate, sulfate, andsulfinate.

Metabolites of the Compounds of the Invention

Also falling within the scope of this invention are the in vivometabolic products of the compounds described herein. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products typically are identified by preparing aradiolabelled (e.g., C¹⁴ or H³) compound of the invention, administeringit parenterally in a detectable dose (e.g., greater than about 0.5mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man,allowing sufficient time for metabolism to occur (typically about 30seconds to 30 hours) and isolating its conversion products from theurine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS or NMR analysis. In general, analysis of metabolites is done in thesame way as conventional drug metabolism studies well-known to thoseskilled in the art. The conversion products, so long as they are nototherwise found in vivo, are useful in diagnostic assays for therapeuticdosing of the compounds of the invention even if they possess noanti-infective activity of their own.

Compounds of the Invention

The definitions and substituents for various genus and subgenus of thepresent compounds are described and illustrated herein. It should beunderstood by one skilled in the art that any combination of thedefinitions and substituents described above should not result in aninoperable species or compound. “Inoperable species or compounds” meanscompound structures that violates relevant scientific principles (suchas, for example, a carbon atom connecting to more than four covalentbonds) or compounds too unstable to permit isolation and formulationinto pharmaceutically acceptable dosage forms.

Pharmaceutical Formulations

The compounds of this invention are formulated with conventionalcarriers and excipients, which will be selected in accord with ordinarypractice. Tablets will contain excipients, glidants, fillers, bindersand the like. Aqueous formulations are prepared in sterile form, andwhen intended for delivery by other than oral administration generallywill be isotonic. All formulations will optionally contain excipientssuch as those set forth in the Handbook of Pharmaceutical Excipients(1986), herein incorporated by reference in its entirety. Excipientsinclude ascorbic acid and other antioxidants, chelating agents such asEDTA, carbohydrates such as dextrin, hydroxyalkylcellulose,hydroxyalkylmethylcellulose, stearic acid and the like. The pH of theformulations ranges from about 2 to about 11, but is ordinarily about 7to 10.

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations. Theformulations of the invention, both for veterinary and for human use,comprise at least one active ingredient, together with one or moreacceptable carriers and optionally other therapeutic ingredients. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and physiologically innocuousto the recipient thereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.), hereinincorporated by reference in its entirety. Such methods include the stepof bringing into association the active ingredient with the carrierwhich constitutes one or more accessory ingredients. In general theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also beadministered as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the active ingredient in a free-flowing form suchas a powder or granules, optionally mixed with a binder, lubricant,inert diluent, preservative, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered active ingredient moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and optionally are formulatedso as to provide slow or controlled release of the active ingredient.

For administration to the eye or other external tissues e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w (including active ingredient(s) in a range between 0.1%and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.),preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither a paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol(including PEG 400) and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethyl sulphoxide andrelated analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties. The cream should preferablybe a non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used, the last three being preferred esters. Thesemay be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils are used.

Pharmaceutical formulations according to the present invention compriseone or more compounds of the invention together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents. Pharmaceutical formulations containing the activeingredient may be in any form suitable for the intended method ofadministration. When used for oral use for example, tablets, troches,lozenges, aqueous or oil suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs may be prepared.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients may be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, lactosemonohydrate, croscarmellose sodium, povidone, calcium or sodiumphosphate; granulating and disintegrating agents, such as maize starch,or alginic acid; binding agents, such as cellulose, microcrystallinecellulose, starch, gelatin or acacia; and lubricating agents, such asmagnesium stearate, stearic acid or talc. Tablets may be uncoated or maybe coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample calcium phosphate or kaolin, or as soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, such aspeanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oral suspensionsmay contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth herein, andflavoring agents may be added to provide a palatable oral preparation.These compositions may be preserved by the addition of an antioxidantsuch as ascorbic acid.

Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water providethe active ingredient in admixture with a dispersing or wetting agent, asuspending agent, and one or more preservatives. Suitable dispersing orwetting agents and suspending agents are exemplified by those disclosedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan monooleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan monooleate. Theemulsion may also contain sweetening and flavoring agents. Syrups andelixirs may be formulated with sweetening agents, such as glycerol,sorbitol or sucrose. Such formulations may also contain a demulcent, apreservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned herein. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for administration to the eye include eye dropswherein the active ingredient is dissolved or suspended in a suitablecarrier, especially an aqueous solvent for the active ingredient. Theactive ingredient is preferably present in such formulations in aconcentration of 0.5 to 20%, advantageously 0.5 to 10% particularlyabout 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 μm (includingparticle sizes in a range between 0.1 and 500 μm in increments such as0.5 μm, 1 μm, 30 μm, 35 μm, etc.), which is administered by rapidinhalation through the nasal passage or by inhalation through the mouthso as to reach the alveolar sacs. Suitable formulations include aqueousor oily solutions of the active ingredient. Formulations suitable foraerosol or dry powder administration may be prepared according toconventional methods and may be delivered with other therapeutic agentssuch as compounds heretofore used in the treatment or prophylaxis ofinfections as described herein.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations are presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

Compounds of the invention can also be formulated to provide controlledrelease of the active ingredient to allow less frequent dosing or toimprove the pharmacokinetic or toxicity profile of the activeingredient. Accordingly, the invention also provided compositionscomprising one or more compounds of the invention formulated forsustained or controlled release.

The effective dose of an active ingredient depends at least on thenature of the condition being treated, toxicity, whether the compound isbeing used prophylactically (lower doses) or against an active diseaseor condition, the method of delivery, and the pharmaceuticalformulation, and will be determined by the clinician using conventionaldose escalation studies. The effective dose can be expected to be fromabout 0.0001 to about 1000 mg/kg body weight per day. For example, thedaily candidate dose for an adult human of approximately 70 kg bodyweight will range from about 0.05 mg to about 100 mg, or between about0.1 mg and about 25 mg, or between about 0.4 mg and about 4 mg, and maytake the form of single or multiple doses.

In yet another embodiment, the present application disclosespharmaceutical compositions comprising a compound of the invention or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or exipient.

Routes of Administration

One or more compounds of the invention (herein referred to as the activeingredients) are administered by any route appropriate to the conditionto be treated. Suitable routes include oral, rectal, nasal, topical(including buccal and sublingual), vaginal and parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural), and the like. It will be appreciated that the preferred routemay vary with for example the condition of the recipient. An advantageof the compounds of this invention is that they are orally bioavailableand can be dosed orally.

Combination Therapy

In one embodiment, the compounds of the present invention are used incombination with an additional active therapeutic ingredient or agent.

In one embodiment, combinations of the compounds of the invention, andadditional active agents may be selected to treat patients with a viralinfection, for example, HBV, HCV, or HIV infection.

Useful active therapeutic agents for HBV include reverse transcriptaseinhibitors, such as lamivudine (Epivir®), adefovir (Hepsera®), tenofovir(Viread®), telbivudine (Tyzeka®), entecavir (Baraclude®), andClevudine®. Other useful active therapeutic agents includeimmunomodulators, such as interferon alpha-2b (Intron A®), pegylatedinterferon alpha-2a (Pegasys®), interferon alpha 2a (Roferon®),interferon alpha N1, prednisone, predinisolone, Thymalfasin®, retinoicacid receptor agonists, 4-methylumbelliferone, Alamifovir®, Metacavir®,Albuferon®, agonists of TLRs (e.g., TLR-7 agonists), and cytokines.

With regard to treatment for HCV, non-limiting examples of suitablecombinations include combinations of one or more compounds of thepresent invention with one or more interferons, ribavirin or itsanalogs, HCV NS3 protease inhibitors, alpha-glucosidase 1 inhibitors,hepatoprotectants, nucleoside or nucleotide inhibitors of HCV NS5Bpolymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5Ainhibitors, TLR-7 agonists, cyclophilin inhibitors, HCV IRES inhibitors,pharmacokinetic enhancers, and other drugs for treating HCV.

More specifically, one or more compounds of the present invention may becombined with one or more compounds selected from the group consistingof

1) interferons, e.g., pegylated rIFN-alpha 2b (PEG-Intron), pegylatedrIFN-alpha 2a (Pegasys), rIFN-alpha 2b (Intron A), rIFN-alpha 2a(Roferon-A), interferon alpha (MOR-22, OPC-18, Alfaferone, Alfanative,Multiferon, subalin), interferon alfacon-1 (Infergen), interferonalpha-n1 (Wellferon), interferon alpha-n3 (Alferon), interferon-beta(Avonex, DL-8234), interferon-omega (omega DUROS, Biomed 510),albinterferon alpha-2b (Albuferon), IFN alpha XL, BLX-883 (Locteron),DA-3021, glycosylated interferon alpha-2b (AVI-005), PEG-Infergen,PEGylated interferon lambda (PEGylated IL-29), and belerofon,

2) ribavirin and its analogs, e.g., ribavirin (Rebetol, Copegus), andtaribavirin (Viramidine),

3) HCV NS3 protease inhibitors, e.g., boceprevir (SCH-503034, SCH-7),telaprevir (VX-950), VX-813, TMC-435 (TMC435350), ABT-450, BI-201335,BI-1230, MK-7009, SCH-900518, VBY-376, VX-500, GS-9256, GS-9451,BMS-790052, BMS-605339, PHX-1766, AS-101, YH-5258, YH5530, YH5531, andITMN-191 (R-7227),

4) alpha-glucosidase 1 inhibitors, e.g., celgosivir (MX-3253), Miglitol,and UT-231 B,

5) hepatoprotectants, e.g., emericasan (IDN-6556), ME-3738, GS-9450(LB-84451), silibilin, and MitoQ,

6) nucleoside or nucleotide inhibitors of HCV NS5B polymerase, e.g.,R1626, R7128 (R4048), IDX184, IDX-102, PSI-7851, BCX-4678,valopicitabine (NM-283), and MK-0608,

7) non-nucleoside inhibitors of HCV NS5B polymerase, e.g., filibuvir(PF-868554), ABT-333, ABT-072, BI-207127, VCH-759, VCH-916, JTK-652,MK-3281, VBY-708, VCH-222, A848837, ANA-598, GL60667, GL59728, A-63890,A-48773, A-48547, BC-2329, VCH-796 (nesbuvir), GSK625433, BILN-1941,XTL-2125, and GS-9190,

8) HCV NS5A inhibitors, e.g., AZD-2836 (A-831), AZD-7295 (A-689), andBMS-790052,

9) TLR-7 agonists, e.g., imiquimod, 852A, GS-9524, ANA-773, ANA-975,AZD-8848 (DSP-3025), PF-04878691, and SM-360320,

10) cyclophillin inhibitors, e.g., DEBIO-025, SCY-635, and NIM811,

11) HCV IRES inhibitors, e.g., MCI-067,

12) pharmacokinetic enhancers, e.g., BAS-100, SPI-452, PF-4194477,TMC-41629, GS-9350, GS-9585, and roxythromycin,

13) other drugs for treating HCV, e.g., thymosin alpha 1 (Zadaxin),nitazoxanide (Alinea, NTZ), BIVN-401 (virostat), PYN-17 (altirex),KPE02003002, actilon (CPG-10101), GS-9525, KRN-7000, civacir, GI-5005,XTL-6865, BIT225, PTX-111, ITX2865, TT-033i, ANA 971, NOV-205, tarvacin,EHC-18, VGX-410C, EMZ-702, AVI 4065, BMS-650032, BMS-791325,Bavituximab, MDX-1106 (ONO-4538), Oglufanide, FK-788, and VX-497(merimepodib).

In addition, the compounds of the invention may be employed incombination with other therapeutic agents for the treatment orprophylaxis of HIV or AIDS and/or one or more other diseases present ina human subject suffering from HIV or AIDS (e.g., bacterial and/orfungal infections, other viral infections such as hepatitis B orhepatitis C, or cancers such as Kaposi's sarcoma). The additionaltherapeutic agent(s) may be coformulated with one or more salts of theinvention (e.g., coformulated in a tablet).

In one embodiment, non-limiting examples of suitable combinationsinclude combinations of one or more compounds of the present inventionwith one or more HIV protease inhibitors, HIV non-nucleoside inhibitorsof reverse transcriptase, HIV nucleoside inhibitors of reversetranscriptase, HIV nucleotide inhibitors of reverse transcriptase, HIVintegrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, entryinhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, CCR5inhibitors, CCR8 inhibitors, RNase H inhibitors, maturation inhibitors,pharmacokinetic enhancers, and other drugs for treating HIV.

More specifically, one or more compounds of the present invention may becombined with one or more compounds selected from the group consistingof

1) HIV protease inhibitors, e.g., amprenavir (Agenerase), atazanavir(Reyataz), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir,ritonavir (norvir), nelfinavir (Viracept), saquinavir (Invirase),tipranavir (Aptivus), brecanavir, darunavir (Prezista), TMC-126,TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649,KNI-272, DPC-681, DPC-684, DG17, GS-8374, MK-8122 (PPL-100), DG35, andAG 1859, SPI-256, TMC 52390, PL-337, SM-322377, SM-309515, GRL-02031,CRS-074, CRS-075, KB-98, and A-790742,

2) HIV non-nucleoside inhibitors of reverse transcriptase, e.g.,capravirine, emivirine, delaviridine (Rescriptor), efavirenz (Sustiva),nevirapine (Viramune), (+)-calanolide A, calanolide B, etravirine(Intelence), GW5634, DPC-083, DPC-961, DPC-963, MIV-150, MIV-160,MIV-170, dapivirine (TMC-120), rilpivirine (TMC-278), BILR 355 BS, VRX840773, UK-453061, and RDEA806, RDEA 427, RDEA 640, IDX 899, ANX-201(Thiovir), R-1206, LOC-dd, IQP-0410 (SJ-3366), YM-215389, YM-228855,CMX-052, and CMX-182,

3) HIV nucleoside inhibitors of reverse transcriptase, e.g., zidovudine(Retrovir), emtricitabine (Emtriva), didanosine (Videx), stavudine(Zerit), zalcitabine (Hivid), lamivudine (Epivir), abacavir (Ziagen),amdoxovir, elvucitabine (ACH 126443), alovudine (MIV-310), MIV-210,racivir (racemic FTC, PSI-5004), D-d4FC, phosphazide, fozivudinetidoxil, apricitibine (AVX754, SPD-754), GS-7340, KP-1461, AVX756,OBP-601, dioxolane thymine, TMC-254072, INK-20, PPI-801, PPI-802,MIV-410, 4′-Ed4T, B-108, and fosalvudine tidoxil (HDP 99.0003),

4) HIV nucleotide inhibitors of reverse transcriptase, e.g., tenofovirdisoproxil fumarate (Viread), and adefovir dipivoxil,

5) HIV integrase inhibitors, e.g., curcumin, derivatives of curcumin,chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid,derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid,derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester,derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives oftyrphostin, quercetin, derivatives of quercetin, S-1360, zintevir(AR-177), L-870812, and L-870810, raltegravir (Isentress, MK-0518),elvitegravir (GS-9137), BMS-538158, GSK364735C, BMS-707035, MK-2048,GSK-349572 (S-349572), GSK-265744 (S-265744), GSK-247303 (S-247303),S-1360 (GW810871), 1,5-DCQA, INH-001, INT-349, V-165, RIN-25, BFX-1001,BFX-1002, BFX-1003, RSC-1838, BCH-33040, and BA 011,

6) gp41 inhibitors, e.g., enfuvirtide (Fuzeon), sifuvirtide, MPI-451936,FB006M, A-329029, and TRI-1144,

7) CXCR4 inhibitors, e.g., AMD-070, KRH-3955 (CS-3955), AMD-9370,AMD-3451, RPI-MN, MSX-122, and POL-2438,

8) entry inhibitors, e.g., SP01A, PA-161, SPC3, TNX-355, DES6, SP-10,SP-03, CT-319, and CT-326,

9) gp120 inhibitors, e.g., BMS-488043 and its prodrugs, BlockAide/CR,KPC-2, and MNLP62,

10) G6PD and NADH-oxidase inhibitors, e.g., immunitin,

11) CCR5 inhibitors, e.g., aplaviroc, nifeviroc, vicriviroc(SCH-417690), maraviroc (Selzentry), PRO-140, PRO-542, INCB15050,INCB9471, PF-232798, SCH-532706, GSK-706769, TAK-652, TAK-220, ESN-196,RO-1752, ZM-688523, AMD-887, YM-370749, NIBR-1282, SCH-350634,ZM-688523, and CCR5mAb004,

12) CCR8 inhibitors, e.g., ZK-756326,

13) RNase H inhibitors, e.g., ODN-93, and ODN-112,

14) maturation inhibitors, e.g., bevirimat (PA-457), PA-040, MPC-9055(vicecon, MPI-49839), ACH-100703, ACH-100706

15) pharmacokinetic enhancers, e.g., BAS-100, SPI-452, PF-4194477,TMC-41629, GS-9350, GS-9585, and roxythromycin,

16) other drugs for treating HIV, e.g., REP 9, SP-01A, TNX-355, DES6,ODN-93, ODN-112, VGV-1, Ampligen, HRG214, Cytolin, VGX-410, VGX-820,KD-247, AMZ 0026, CYT 99007, A-221 HIV, HPH-116, DEBIO-025, BAY 50-4798,MDX010 (ipilimumab), PBS 119, BIT-225, UBT-8147, ITI-367, AFX-400,BL-1050, GRN-139951, GRN-140665, AX-38679, RGB-340638, PPI-367, and ALG889.

Where the disorder is cancer, combination with at least one otheranticancer therapy is envisaged. In particular, in anti-cancer therapy,combination with other anti-neoplastic agent (includingchemotherapeutic, hormonal or antibody agents) is envisaged as well ascombination with surgical therapy and radiotherapy. Combinationtherapies according to the present invention thus comprise theadministration of at least one compound of the invention or a salt orsolvate thereof, and the use of at least one other cancer treatmentmethod. Preferably, combination therapies according to the presentinvention comprise the administration of at least one compound of theinvention or a salt or solvate thereof, and at least one otherpharmaceutically active agent, preferably an anti-neoplastic agent. Thecompounds) of the invention and the other pharmaceutically activeagent(s) may be administered together or separately and, whenadministered separately this may occur simultaneously or sequentially inany order (including administration on different days according to thetherapy regimen) and by any convenient route. The amounts of thecompound(s) of the invention and the other pharmaceutically activeagent(s) and the relative timings of administration will be selected inorder to achieve the desired combined therapeutic effect.

In one embodiment, the further anti-cancer therapy is at least oneadditional antineoplastic agent. Any anti-neoplastic agent that hasactivity versus a susceptible tumor being treated may be utilized in thecombination. Typical anti-neoplastic agents useful include, but are notlimited to, anti-microtubule agents such as diterpenoids and vincaalkaloids; platinum coordination complexes; alkylating agents such asnitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, andtriazenes; antibiotic agents such as anthracyclins, actinomycins andbleomycins; topoisomerase II inhibitors such as epipodophyllotoxins;antimetabolites such as purine and pyrimidine analogues and anti-folatecompounds; topoisomerase I inhibitors such as camptothecins; hormonesand hormonal analogues; signal transduction pathway inhibitors;nonreceptor tyrosine kinase angiogenesis inhibitors; immunotherapeuticagents; proapoptotic agents; and cell cycle signaling inhibitors.

Anti-microtubule or anti-mitotic agents are phase specific agents activeagainst the microtubules of tumor cells during M or the mitosis phase ofthe cell cycle. Examples of anti-microtubule agents include, but are notlimited to, diterpenoids and vinca alkaloids.

Diterpenoids, which are derived from natural sources, are phase specificanti -cancer agents that operate at the G₂/M phases of the cell cycle.It is believed that the diterpenoids stabilize the β-tubulin subunit ofthe microtubules, by binding with this protein. Disassembly of theprotein appears then to be inhibited with mitosis being arrested andcell death following. Examples of diterpenoids include, but are notlimited to, paclitaxel and its analog docetaxel.

Paclitaxel, 5β,20-epoxy-1,2a,4,7β,10β,13a-hexa-hydroxytax-11-en-9-one4,10-diacetate 2-benzoate 13-ester with(2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene productisolated from the Pacific yew tree Taxus brevifolia and is commerciallyavailable as an injectable solution TAXOL®. It is a member of the taxanefamily of terpenes. Paclitaxel has been approved for clinical use in thetreatment of refractory ovarian cancer in the United States (Markman etal., Yale Journal of Biology and Medicine, 64:583, 1991; McGuire et al.,Ann. Intern, Med., 11 1:273, 1989) and for the treatment of breastcancer (Holmes et al., J. Nat. Cancer Inst., 83:1797, 1991.) It is apotential candidate for treatment of neoplasms in the skin (Einzig et.al., Proc. Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas(Forastire et. al., Sem. Oncol., 20:56, 1990). The compound also showspotential for the treatment of polycystic kidney disease (Woo et. al.,Nature, 368:750. 1994), lung cancer and malaria. Treatment of patientswith paclitaxel results in bone marrow suppression (multiple celllineages, Ignoff, R J. et. al, Cancer Chemotherapy Pocket Guide_(A)1998) related to the duration of dosing above a threshold concentration(50 nM) (Kearns, C M. et. al., Seminars in Oncology, 3(6) p. 16-23,1995).

Docetaxel, (2R,3S)—N-carboxy-3-phenylisoserine, N-te/f-butyl ester,13-ester with 5β-20-epoxy-1,2a,4,7β,10β,13a-hexahydroxytax-11-en-9-one4-acetate 2-benzoate, trihydrate; is commercially available as aninjectable solution as TAXOTERE®. Docetaxel is indicated for thetreatment of breast cancer. Docetaxel is a semisynthetic derivative ofpaclitaxel q.v., prepared using a natural precursor,10-deacetyl-baccatin III, extracted from the needle of the European Yewtree.

Vinca alkaloids are phase specific anti-neoplastic agents derived fromthe periwinkle plant. Vinca alkaloids act at the M phase (mitosis) ofthe cell cycle by binding specifically to tubulin. Consequently, thebound tubulin molecule is unable to polymerize into microtubules.Mitosis is believed to be arrested in metaphase with cell deathfollowing. Examples of vinca alkaloids include, but are not limited to,vinblastine, vincristine, and vinorelbine.

Vinblastine, vincaleukoblastine sulfate, is commercially available asVELBAN® as an injectable solution. Although, it has possible indicationas a second line therapy of various solid tumors, it is primarilyindicated in the treatment of testicular cancer and various lymphomasincluding Hodgkin's Disease; and lymphocytic and histiocytic lymphomas.Myelosuppression is the dose limiting side effect of vinblastine.Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commerciallyavailable as ONCOVIN® as an injectable solution. Vincristine isindicated for the treatment of acute leukemias and has also found use intreatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas.Alopecia and neurologic effects are the most common side effect ofvincristine and to a lesser extent myelosupression and gastrointestinalmucositis effects occur.

Vinorelbine, 3′,4′-didehydro-4′-deoxy-C′-norvincaleukoblastine[R—(R*,R*)-2,3-dihydroxybutanedioate (1:2) (salt)], commerciallyavailable as an injectable solution of vinorelbine tartrate(NAVELBINE®), is a semisynthetic vinca alkaloid. Vinorelbine isindicated as a single agent or in combination with otherchemotherapeutic agents, such as cisplatin, in the treatment of varioussolid tumors, particularly non-small cell lung, advanced breast, andhormone refractory prostate cancers. Myelosuppression is the most commondose limiting side effect of vinorelbine.

Platinum coordination complexes are non-phase specific anti-canceragents, which are interactive with DNA. The platinum complexes entertumor cells, undergo, aquation and form intra- and interstrandcrosslinks with DNA causing adverse biological effects to the tumor.Examples of platinum coordination complexes include, but are not limitedto, oxaliplatin, cisplatin and carboplatin. Cisplatin,cis-diamminedichloroplatinum, is commercially available as PLATINOL® asan injectable solution. Cisplatin is primarily indicated in thetreatment of metastatic testicular and ovarian cancer and advancedbladder cancer. Carboplatin, platinum, diammine[1,1-cyclobutane-dicarboxylate(2-)O,O′], is commercially available asPARAPLATIN® as an injectable solution. Carboplatin is primarilyindicated in the first and second line treatment of advanced ovariancarcinoma.

Alkylating agents are non-phase anti-cancer specific agents and strongelectrophiles. Typically, alkylating agents form covalent linkages, byalkylation, to DNA through nucleophilic moieties of the DNA moleculesuch as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazolegroups. Such alkylation disrupts nucleic acid function leading to celldeath. Examples of alkylating agents include, but are not limited to,nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil;alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; andtriazenes such as dacarbazine. Cyclophosphamide,2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxidemonohydrate, is commercially available as an injectable solution ortablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent orin combination with other chemotherapeutic agents, in the treatment ofmalignant lymphomas, multiple myeloma, and leukemias. Melphalan,4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially availableas an injectable solution or tablets as ALKERAN®. Melphalan is indicatedfor the palliative treatment of multiple myeloma and non-resectableepithelial carcinoma of the ovary. Bone marrow suppression is the mostcommon dose limiting side effect of melphalan. Chlorambucil,4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commerciallyavailable as LEUKERAN® tablets. Chlorambucil is indicated for thepalliative treatment of chronic lymphatic leukemia, and malignantlymphomas such as lymphosarcoma, giant follicular lymphoma, andHodgkin's disease. Busulfan, 1,4-butanediol dimethanesulfonate, iscommercially available as MYLERAN® TABLETS. Busulfan is indicated forthe palliative treatment of chronic myelogenous leukemia. Carmustine,1,3-[bis(2-chloroethyl)-1-nitrosourea, is commercially available assingle vials of lyophilized material as BiCNU®. Carmustine is indicatedfor the palliative treatment as a single agent or in combination withother agents for brain tumors, multiple myeloma, Hodgkin's disease, andnon-Hodgkin's lymphomas. Dacarbazine,5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, is commerciallyavailable as single vials of material as DTIC-Dome®. Dacarbazine isindicated for the treatment of metastatic malignant melanoma and incombination with other agents for the second line treatment of Hodgkin'sDisease.

Antibiotic anti-neoplasties are non-phase specific agents, which bind orintercalate with DNA. Typically, such action results in stable DNAcomplexes or strand breakage, which disrupts ordinary function of thenucleic acids leading to cell death. Examples of antibioticanti-neoplastic agents include, but are not limited to, actinomycinssuch as dactinomycin, anthrocyclins such as daunorubicin anddoxorubicin; and bleomycins. Dactinomycin, also know as Actinomycin D,is commercially available in injectable form as COSMEGEN®. Dactinomycinis indicated for the treatment of Wilm's tumor and rhabdomyosarcoma.Daunorubicin,(8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12naphthacenedione hydrochloride, is commercially available as a liposomalinjectable form as DAUNOXOME® or as an injectable as CERUBIDINE®.Daunorubicin is indicated for remission induction in the treatment ofacute nonlymphocytic leukemia and advanced HIV associated Kaposi'ssarcoma. Doxorubicin,(8S,10S)-10-[(3-amino-2,3,6-trideoxy-a-L-lyxo-hexopyranosyl)oxy]-8-glycoloyl,7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12 naphthacenedionehydrochloride, is commercially available as an injectable form as RUBEX®or ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for the treatmentof acute lymphoblastic leukemia and acute myeloblasts leukemia, but isalso a useful component in the treatment of some solid tumors andlymphomas. Bleomycin, a mixture of cytotoxic glycopeptide antibioticsisolated from a strain of Streptomyces verticillus, is commerciallyavailable as BLENOXAN E®. Bleomycin is indicated as a palliativetreatment, as a single agent or in combination with other agents, ofsquamous cell carcinoma, lymphomas, and testicular carcinomas.

Topoisomerase II inhibitors include, but are not limited to,epipodophyllotoxins. Epipodophyllotoxins are phase specificanti-neoplastic agents derived from the mandrake plant.Epipodophyllotoxins typically affect cells in the S and G₂ phases of thecell cycle by forming a ternary complex with topoisomerase II and DNAcausing DNA strand breaks. The strand breaks accumulate and cell deathfollows. Examples of epipodophyllotoxins include, but are not limitedto, etoposide and teniposide. Etoposide, 4′-demethyl-epipodophyllotoxin9[4,6-0-(R)-ethylidene-β-D-glucopyranoside], is commercially availableas an injectable solution or capsules as VePESID® and is commonly knownas VP-16. Etoposide is indicated as a single agent or in combinationwith other chemotherapy agents in the treatment of testicular andnon-small cell lung cancers. Teniposide, 4′-demethyl-epipodophyllotoxin9[4,6-0-(R)-thenylidene-β-D-glucopyranoside], is commercially availableas an injectable solution as VUMON® and is commonly known as VM-26.Teniposide is indicated as a single agent or in combination with otherchemotherapy agents in the treatment of acute leukemia in children.

Antimetabolite neoplastic agents are phase specific anti-neoplasticagents that act at S phase (DNA synthesis) of the cell cycle byinhibiting DNA synthesis or by inhibiting purine or pyrimidine basesynthesis and thereby limiting DNA synthesis. Consequently, S phase doesnot proceed and cell death follows. Examples of antimetaboliteanti-neoplastic agents include, but are not limited to, fluorouracil,methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.5-fluorouracil, 5-fluoro-2,4-(1H,3H)pyrimidinedione, is commerciallyavailable as fluorouracil. Administration of 5-fluorouracil leads toinhibition of thymidylate synthesis and is also incorporated into bothRNA and DNA. The result typically is cell death. 5-fluorouracil isindicated as a single agent or in combination with other chemotherapyagents in the treatment of carcinomas of the breast, colon, rectum,stomach and pancreas. Other fluoropyrimidine analogs include 5-fluorodeoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.

Cytarabine, 4-amino-1-β-D-arabinofuranosyl-2(I H)-pyrimidinone, iscommercially available as CYTOSAR-U® and is commonly known as Ara-C. Itis believed that cytarabine exhibits cell phase specificity at S-phaseby inhibiting DNA chain elongation by terminal incorporation ofcytarabine into the growing DNA chain. Cytarabine is indicated as asingle agent or in combination with other chemotherapy agents in thetreatment of acute leukemia. Other cytidine analogs include5-azacytidine and 2′,2′-difluorodeoxycytidine (gemcitabine).Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate, iscommercially available as PURINETHOL®. Mercaptopurine exhibits cellphase specificity at S-phase by inhibiting DNA synthesis by an as of yetunspecified mechanism. Mercaptopurine is indicated as a single agent orin combination with other chemotherapy agents in the treatment of acuteleukemia. A useful mercaptopurine analog is azathioprine. Thioguanine,2-amino-1,7-dihydro-6H-purine-6-thione, is commercially available asTABLOID®. Thioguanine exhibits cell phase specificity at S-phase byinhibiting DNA synthesis by an as of yet unspecified mechanism.Thioguanine is indicated as a single agent or in combination with otherchemotherapy agents in the treatment of acute leukemia. Other purineanalogs include pentostatin, erythrohydroxynonyladenine, fludarabinephosphate, and cladribine. Gemcitabine, 2′-deoxy-2′,2′-difluorocytidinemonohydrochloride (β-isomer), is commercially available as GEMZAR®.Gemcitabine exhibits cell phase specificity at S-phase and by blockingprogression of cells through the G1/S boundary. Gemcitabine is indicatedin combination with cisplatin in the treatment of locally advancednon-small cell lung cancer and alone in the treatment of locallyadvanced pancreatic cancer. Methotrexate,N-[4[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamicacid, is commercially available as methotrexate sodium. Methotrexateexhibits cell phase effects specifically at S-phase by inhibiting DNAsynthesis, repair and/or replication through the inhibition ofdyhydrofolic acid reductase which is required for synthesis of purinenucleotides and thymidylate. Methotrexate is indicated as a single agentor in combination with other chemotherapy agents in the treatment ofchoriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, andcarcinomas of the breast, head, neck, ovary and bladder.

Camptothecins, including, camptothecin and camptothecin derivatives areavailable or under development as Topoisomerase I inhibitors.Camptothecins cytotoxic activity is believed to be related to itsTopoisomerase I inhibitory activity. Examples of camptothecins include,but are not limited to irinotecan, topotecan, and the various opticalforms of7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecindescribed below. Irinotecan HCl,(4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)carbonyloxy]-1H-pyrano[3′,4′,6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dionehydrochloride, is commercially available as the injectable solutionCAMPTOSAR®. Irinotecan is a derivative of camptothecin which binds,along with its active metabolite SN-38, to the topoisomerase I—DNAcomplex. It is believed that cytotoxicity occurs as a result ofirreparable double strand breaks caused by interaction of thetopoisomerase I: DNA: irintecan or SN-38 ternary complex withreplication enzymes. Irinotecan is indicated for treatment of metastaticcancer of the colon or rectum. Topotecan HCl,(S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′,6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dionemonohydrochloride, is commercially available as the injectable solutionHYCAMTI N®. Topotecan is a derivative of camptothecin which binds to thetopoisomerase I—DNA complex and prevents religation of singles strandbreaks caused by Topoisomerase I in response to torsional strain of theDNA molecule. Topotecan is indicated for second line treatment ofmetastatic carcinoma of the ovary and small cell lung cancer.

Hormones and hormonal analogues are useful compounds for treatingcancers in which there is a relationship between the hormone(s) andgrowth and/or lack of growth of the cancer. Examples of hormones andhormonal analogues useful in cancer treatment include, but are notlimited to, adrenocorticosteroids such as prednisone and prednisolonewhich are useful in the treatment of malignant lymphoma and acuteleukemia in children; aminoglutethimide and other aromatase inhibitorssuch as anastrozole, letrazole, vorazole, and exemestane useful in thetreatment of adrenocortical carcinoma and hormone dependent breastcarcinoma containing estrogen receptors; progestrins such as megestrolacetate useful in the treatment of hormone dependent breast cancer andendometrial carcinoma; estrogens, androgens, and anti-androgens such asflutamide, nilutamide, bicalutamide, cyproterone acetate and5a-reductases such as finasteride and dutasteride, useful in thetreatment of prostatic carcinoma and benign prostatic hypertrophy;anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene,iodoxyfene, as well as selective estrogen receptor modulators (SERMS)such those described in U.S. Pat. Nos. 5,681,835, 5,877,219, and6,207,716, useful in the treatment of hormone dependent breast carcinomaand other susceptible cancers; and gonadotropin-releasing hormone (GnRH)and analogues thereof which stimulate the release of leutinizing hormone(LH) and/or follicle stimulating hormone (FSH) for the treatmentprostatic carcinoma, for instance, LHRH agonists and antagagonists suchas goserelin acetate and luprolide.

Signal transduction pathway inhibitors are those inhibitors, which blockor inhibit a chemical process which evokes an intracellular change. Asused herein this change is cell proliferation or differentiation. Signaltranduction inhibitors useful in the present invention includeinhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases,SH2/SH3domain blockers, serine/threonine kinases, phosphotidylinositol-3 kinases, myo-inositol signaling, and Ras oncogenes.

Several protein tyrosine kinases catalyse the phosphorylation ofspecific tyrosyl residues in various proteins involved in the regulationof cell growth. Such protein tyrosine kinases can be broadly classifiedas receptor or non-receptor kinases.

Receptor tyrosine kinases are transmembrane proteins having anextracellular ligand binding domain, a transmembrane domain, and atyrosine kinase domain. Receptor tyrosine kinases are involved in theregulation of cell growth and are generally termed growth factorreceptors. Inappropriate or uncontrolled activation of many of thesekinases, i.e. aberrant kinase growth factor receptor activity, forexample by over-expression or mutation, has been shown to result inuncontrolled cell growth. Accordingly, the aberrant activity of suchkinases has been linked to malignant tissue growth. Consequently,inhibitors of such kinases could provide cancer treatment methods.Growth factor receptors include, for example, epidermal growth factorreceptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2,erbB4, ret, vascular endothelial growth factor receptor (VEGFr),tyrosine kinase with immunoglobulin-like and epidermal growth factorhomology domains (TIE-2), insulin growth factor-I (IGFI) receptor,macrophage colony stimulating factor (cfms), BTK, skit, cmet, fibroblastgrowth factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC),ephrin (eph) receptors, and the RET protooncogene. Several inhibitors ofgrowth receptors are under development and include ligand antagonists,antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides.Growth factor receptors and agents that inhibit growth factor receptorfunction are described, for instance, in Kath, John C, Exp. Opin. Ther.Patents (2000) 10(6):803-818; Shawver et al DDT Vol 2, No. 2 February1997; and Lofts, F. J. et al, “Growth factor receptors as targets”, NewMolecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr,David, CRC press 1994, London.

Tyrosine kinases, which are not growth factor receptor kinases aretermed nonreceptor tyrosine kinases. Non-receptor tyrosine kinasesuseful in the present invention, which are targets or potential targetsof anti-cancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focaladhesion kinase), Brutons tyrosine kinase, and Bcr-Abl. Suchnon-receptor kinases and agents which inhibit non-receptor tyrosinekinase function are described in Sinh, S. and Corey, S. J., (1999)Journal of Hematotherapy and Stem Cell Research 8 (5): 465-80; andBolen, J. B., Brugge, J. S., (1997) Annual review of Immunology. 15:371-404. SH2/SH3 domain blockers are agents that disrupt SH2 or SH3domain binding in a variety of enzymes or adaptor proteins including,PI3-K p85 subunit, Src family kinases, adaptor molecules (She, Crk, Nek,Grb2) and Ras-GAP. SH2/SH3 domains as targets for anti-cancer drugs arediscussed in Smithgall, T. E. (1995), Journal of Pharmacological andToxicological Methods. 34(3) 125-32.

Inhibitors of Serine/Threonine Kinases including MAP kinase cascadeblockers which include blockers of Raf kinases (rafk), Mitogen orExtracellular Regulated Kinase (MEKs), and Extracellular RegulatedKinases (ERKs); and Protein kinase C family member blockers includingblockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta).IkB kinase family (IKKa, IKKb), PKB family kinases, akt kinase familymembers, and TGF beta receptor kinases. Such Serine/Threonine kinasesand inhibitors thereof are described in Yamamoto, T., Taya, S.,Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt,P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60. 1101-1107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys. 27:41-64;Philip, P. A., and Harris, A. L. (1995), Cancer Treatment and Research.78: 3-27, Lackey, K. et al Bioorganic and Medicinal Chemistry Letters,(10), 2000, 223-226; U.S. Pat. No. 6,268,391; and Martinez-Iacaci, L.,et al, Int. J. Cancer (2000), 88(1), 44-52.

Inhibitors of Phosphotidyl inositol-3 Kinase family members includingblockers of PI3-kinase, ATM, DNA-PK, and Ku are also useful in thepresent invention. Such kinases are discussed in Abraham, R T. (1996),Current Opinion in Immunology. 8 (3) 412-8; Canman, C. E., Lim, D. S.(1998), Oncogene 17 (25) 3301-3308; Jackson, S. P. (1997), InternationalJournal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. etal, Cancer res, (2000) 60(6), 1541-1545.

Also useful in the present invention are Myo-inositol signalinginhibitors such as phospholipase C blockers and Myoinositol analogues.Such signal inhibitors are described in Powis, G., and Kozikowski A.,(1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workmanand David Kerr, CRC press 1994, London.

Another group of signal transduction pathway inhibitors are inhibitorsof Ras Oncogene. Such inhibitors include inhibitors offarnesyltransferase, geranyl-geranyl transferase, and CAAX proteases aswell as anti-sense oligonucleotides, ribozymes and immunotherapy. Suchinhibitors have been shown to block ras activation in cells containingwild type mutant ras, thereby acting as antiproliferation agents. Rasoncogene inhibition is discussed in Scharovsky, O. G., Rozados, V. R.,Gervasoni, S. I. Matar, P. (2000), Journal of Biomedical Science. 7(4)292-8; Ashby, M. N. (1998), Current Opinion in Lipidology. 9 (2) 99-102;and BioChim. Biophys. Acta, (19899) 1423(3):19-30.

As mentioned above, antibody antagonists to receptor kinase ligandbinding may also serve as signal transduction inhibitors. This group ofsignal transduction pathway inhibitors includes the use of humanizedantibodies to the extracellular ligand binding domain of receptortyrosine kinases. For example Imclone C225 EGFR specific antibody (seeGreen, M. C. et al, Monoclonal Antibody Therapy for Solid Tumors, CancerTreat. Rev., (2000), 26(4), 269-286); Herceptin® erbB2 antibody (seeTyrosine Kinase Signalling in Breast cancep erbB Family ReceptorTyrosine Kniases, Breast cancer Res., 2000, 2(3), 176-183); and 2CBVEGFR2 specific antibody (see Brekken, R. A. et al, Selective Inhibitionof VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumorgrowth in mice, Cancer Res. (2000) 60, 51 17-5124).

Anti-angiogenic agents including non-receptor kinase angiogenesisinhibitors may also be useful. Anti-angiogenic agents such as thosewhich inhibit the effects of vascular edothelial growth factor, (forexample the anti-vascular endothelial cell growth factor antibodybevacizumab [Avastin™], and compounds that work by other mechanisms (forexample linomide, inhibitors of integrin avβ3 function, endostatin andangiostatin).

Agents used in immunotherapeutic regimens may also be useful incombination with the compounds of formula (I). Immunotherapy approaches,including for example ex-vivo and in-vivo approaches to increase theimmunogenecity of patient tumour cells, such as transfection withcytokines such as interleukin 2, interleukin 4 or granulocyte-macrophagecolony stimulating factor, approaches to decrease T-cell anergy,approaches using transfected immune cells such as cytokine-transfecteddendritic cells, approaches using cytokine-transfected tumour cell linesand approaches using anti-idiotypic antibodies.

Agents used in proapoptotic regimens (e.g., bcl-2 antisenseoligonucleotides) may also be used in the combination of the presentinvention.

Cell cycle signalling inhibitors inhibit molecules involved in thecontrol of the cell cycle. A family of protein kinases called cyclindependent kinases (CDKs) and their interaction with a family of proteinstermed cyclins controls progression through the eukaryotic cell cycle.The coordinate activation and inactivation of different cyclin/CDKcomplexes is necessary for normal progression through the cell cycle.Several inhibitors of cell cycle signalling are under development. Forinstance, examples of cyclin dependent kinases, including CDK2, CDK4,and CDK6 and inhibitors for the same are described in, for instance,Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230.

For the treatment or prophylaxis of pulmonary disorders,anticholinergics of potential use in treating asthma, COPD, bronchitis,and the like, and therefore useful as an additional therapeutic agentinclude antagonists of the muscarinic receptor (particularly of the M3subtype) which have shown therapeutic efficacy in man for the control ofcholinergic tone in COPD (Witek, 1999);1-{4-Hydroxy-1-[3,3,3-tris-(4-fluoro-phenyl)-propionyl]-pyrrolidine-2-carbonyl}-pyrrolidine-2-carboxylicacid (1-methyl-piperidin-4-ylmethyl)-amide;3-[3-(2-Diethylamino-acetoxy)-2-phenyl-propionyloxyl-8-isopropyl-8-methyl-8-azonia-bicyclo[3.2.1]octane(Ipratropium-N,N-diethylglycinate);1-Cyclohexyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid1-aza-bicyclo[2.2.2]oct-3-yl ester (Solifenacin);2-Hydroxymethyl-4-methanesulfinyl-2-phenyl-butyric acid1-aza-bicyclo[2.2.2]oct-3-yl ester (Revatropate);2-{1-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-pyrrolidin-3-yl}-2,2-diphenyl-acetamide(Darifenacin); 4-Azepan-1-yl-2,2-diphenyl-butyramide (Buzepide);7-[3-(2-Diethylamino-acetoxy)-2-phenyl-propionyloxy]-9-ethyl-9-methyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane(Oxitropium-N,N-diethylglycinate);7-[2-(2-Diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-9,9-dimethyl-3-oxa-9-azonia-tricyclo[3.3.1.02,4]nonane(Tiotropium-N,N-diethylglycinate); Dimethylamino-acetic acid2-(3-diisopropylamino-1-phenyl-propyl)-4-methyl-phenyl ester(Tolterodine-N,N-dimethylglycinate);3-[4,4-Bis-(4-fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-1-methyl-1-(2-oxo-2-pyridin-2-yl-ethyl)-pyrrolidinium;1-[1-(3-Fluoro-benzyl)-piperidin-4-yl]-4,4-bis-(4-fluoro-phenyl)-imidazolidin-2-one;1-Cyclooctyl-3-(3-methoxy-1-aza-bicyclo[2.2.2]oct-3-yl)-1-phenyl-prop-2-yn-1-ol;3-[2-(2-Diethylamino-acetoxy)-2,2-di-thiophen-2-yl-acetoxy]-1-(3-phenoxy-propyl)-1-azonia-bicyclo[2.2.2]octane(Aclidinium-N,N-diethyiglycinate); or(2-Diethylamino-acetoxy)-di-thiophen-2-yl-acetic acid1-methyl-1-(2-phenoxy-ethyl)-piperidin-4-yl ester; beta-2 agonist usedto treat broncho-constriction in asthma, COPD and bronchitis includesalmeterol and albuterol; anti-inflammatory signal transductionmodulators for asthma.

With regard to the pulmonary condition of asthma, those skilled in theart appreciate that asthma is a chronic inflammatory disease of theairways resulting from the infiltration of pro-inflammatory cells,mostly eosinophils and activated T-lymphocytes into the bronchial mucosaand submucosa. The secretion of potent chemical mediators, includingcytokines, by these proinflammatory cells alters mucosal permeability,mucus production, and causes smooth muscle contraction. All of thesefactors lead to an increased reactivity of the airways to a wide varietyof irritant stimuli (Kaliner, 1988). Targeting signal transductionpathways is an attractive approach to treating inflammatory diseases, asthe same pathways are usually involved in several cell types andregulate several coordinated inflammatory processes, hence modulatorshave the prospect of a wide spectrum of beneficial effects. Multipleinflammatory signals activate a variety of cell surface receptors thatactivate a limited number of signal transduction pathways, most of whichinvolve cascades of kinases. These kinases in turn may activatetranscription factors that regulate multiple inflammatory genes.Applying “anti-inflammatory signal transduction modulators” (referred toin this text as AISTM), like phosphodiesterase inhibitors (e.g. PDE-4,PDE-5, or PDE-7 specific), transcription factor inhibitors (e.g.blocking NFκB through IKK inhibition), or kinase inhibitors (e.g.blocking P38 MAP, JNK, PI3K, EGFR or Syk) is a logical approach toswitching off inflammation as these small molecules target a limitednumber of common intracellular pathways—those signal transductionpathways that are critical points for the anti-inflammatory therapeuticintervention (see review by P. J. Barnes, 2006).

Additional therapeutic agents include:5-(2,4-Difluoro-phenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid(2-dimethylamino-ethyl)-amide (P38 Map kinase inhibitor ARRY-797);3-Cyclopropylmethoxy-N-(3,5-dichloro-pyridin-4-yl)-4-difluorormethoxy-benzamide(PDE-4 inhibitor Roflumilast);4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenyl-ethyl]-pyridine (PDE-4inhibitor CDP-840);N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)-8-[(methylsulfonyl)amino]-1-dibenzofurancarboxamide(PDE-4 inhibitor Oglemilast);N-(3,5-Dichloro-pyridin-4-yl)-2-[1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl]-2-oxo-acetamide(PDE-4 inhibitor AWD 12-281);8-Methoxy-2-trifluoromethyl-quinoline-5-carboxylic acid(3,5-dichloro-1-oxy-pyridin-4-yl)-amide (PDE-4 inhibitor Sch 351591);4-[5-(4-Fluorophenyl)-2-(4-methanesulfinyl-phenyl)-1H-imidazol-4-yl]-pyridine(P38 inhibitor SB-203850);4-[4-(4-Fluoro-phenyl)-1-(3-phenyl-propyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-but-3-yn-1-ol(P38 inhibitor RWJ-67657);4-Cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-cyclohexanecarboxylic acid2-diethylamino-ethyl ester (2-diethyl-ethyl ester prodrug of Cilomilast,PDE-4 inhibitor);(3-Chloro-4-fluorophenyl)-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-amine(Gefitinib, EGFR inhibitor); and4-(4-Methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide(Imatinib, EGFR inhibitor).

Moreover, asthma is a chronic inflammatory disease of the airwaysproduced by the infiltration of pro-inflammatory cells, mostlyeosinophils and activated T-lymphocytes (Poston, Am. Rev. Respir. Dis.,145 (4 Pt 1), 918-921, 1992; Walker, J. Allergy Olin. Immunol., 88 (6),935-42, 1991) into the bronchial mucosa and submucosa. The secretion ofpotent chemical mediators, including cytokines, by these proinflammatorycells alters mucosal permeability, mucus production, and causes smoothmuscle contraction. All of these factors lead to an increased reactivityof the airways to a wide variety of irritant stimuli (Kaliner,“Bronchial asthma, Immunologic diseases” E. M. Samter, Boston, Little,Brown and Company: 117-118. 1988).

Glucocorticoids, which were first introduced as an asthma therapy in1950 (Carryer, Journal of Allergy, 21, 282-287, 1950), remain the mostpotent and consistently effective therapy for this disease, althoughtheir mechanism of action is not yet fully understood (Morris, J.Allergy Clin. Immunol., 75 (1 Pt) 1-13, 1985). Unfortunately, oralglucocorticoid therapies are associated with profound undesirable sideeffects such as truncal obesity, hypertension, glaucoma, glucoseintolerance, acceleration of cataract formation, bone mineral loss, andpsychological effects, all of which limit their use as long-termtherapeutic agents (Goodman and Gilman, 10th edition, 2001). A solutionto systemic side effects is to deliver steroid drugs directly to thesite of inflammation. Inhaled corticosteroids (ICS) have been developedto mitigate the severe adverse effects of oral steroids. While ICS arevery effective in controlling inflammation in asthma, they too are notprecisely delivered to the optimal site of action in the lungs andproduce unwanted side effects in the mouth and pharynx (candidiasis,sore throat, dysphonia). Combinations of inhaled β2-adrenoreceptoragonist bronchodilators such as formoterol or salmeterol with ICS's arealso used to treat both the bronchoconstriction and the inflammationassociated with asthma and COPD (Symbicort® and Advair®, respectively).However, these combinations have the side effects of both the ICS's andthe β2-adrenoreceptor agonist because of systemic absorption(tachycardia, ventricular dysrhythmias, hypokalemia) primarily becauseneither agent is delivered to the optimal sites of actions in the lungs.In consideration of all problems and disadvantages connected with theadverse side effect profile of ICS and of β2-agonists it would be highlyadvantageous to provide mutual steroid-β2-agonist prodrug to mask thepharmacological properties of both steroids and β2-agonists until such aprodrug reaches the lungs, thereby mitigating the oropharyngeal sideeffects of ICS and cardiovascular side-effects of β2-agonists. In oneaspect, such a mutual steroid-β2-agonist prodrug would be effectivelydelivered to the endobronchial space and converted to active drugs bythe action of lung enzymes, thereby delivering to the site ofinflammation and bronchoconstriction a therapeutic amount of both drugs.An anti-inflammatory agent for combination therapy includesdexamethasone, dexamethasone sodium phosphate, fluorometholone,fluorometholone acetate, loteprednol, loteprednol etabonate,hydrocortisone, prednisolone, fludrocortisones, triamcinolone,triamcinolone acetonide, betamethasone, beclomethasone diproprionate,methylprednisolone, fluocinolone, fluocinolone acetonide, flunisolide,fluocortin-21-butylate, flumethasone, flumetasone pivalate, budesonide,halobetasol propionate, mometasone furoate, fluticasone propionate,ciclesonide; or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present application disclosespharmaceutical compositions comprising a compound of the presentinvention, or a pharmaceutically acceptable salt thereof, in combinationwith at least one additional active agent, and a pharmaceuticallyacceptable carrier or excipient. In yet another embodiment, the presentapplication provides a combination pharmaceutical agent with two or moretherapeutic agents in a unitary dosage form. Thus, it is also possibleto combine any compound of the invention with one or more other activeagents in a unitary dosage form.

The combination therapy may be administered as a simultaneous orsequential regimen. When administered sequentially, the combination maybe administered in two or more administrations.

Co-administration of a compound of the invention with one or more otheractive agents generally refers to simultaneous or sequentialadministration of a compound of the invention and one or more otheractive agents, such that therapeutically effective amounts of thecompound of the invention and one or more other active agents are bothpresent in the body of the patient.

Co-administration includes administration of unit dosages of thecompounds of the invention before or after administration of unitdosages of one or more other active agents, for example, administrationof the compounds of the invention within seconds, minutes, or hours ofthe administration of one or more other active agents. For example, aunit dose of a compound of the invention can be administered first,followed within seconds or minutes by administration of a unit dose ofone or more other active agents. Alternatively, a unit dose of one ormore other active agents can be administered first, followed byadministration of a unit dose of a compound of the invention withinseconds or minutes. In some cases, it may be desirable to administer aunit dose of a compound of the invention first, followed, after a periodof hours (e.g., 1-12 hours), by administration of a unit dose of one ormore other active agents. In other cases, it may be desirable toadminister a unit dose of one or more other active agents first,followed, after a period of hours (e.g., 1-12 hours), by administrationof a unit dose of a compound of the invention.

The combination therapy may provide “synergy” and “synergistic effect”,i.e. the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect may be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined formulation; (2) delivered by alternationor in parallel as separate formulations; or (3) by some other regimen.When delivered in alternation therapy, a synergistic effect may beattained when the compounds are administered or delivered sequentially,e.g., in separate tablets, pills or capsules, or by different injectionsin separate syringes. In general, during alternation therapy, aneffective dosage of each active ingredient is administered sequentially,i.e. serially, whereas in combination therapy, effective dosages of twoor more active ingredients are administered together.

Methods of Treatment

As used herein, an “agonist” is a substance that stimulates its bindingpartner, typically a receptor. Stimulation is defined in the context ofthe particular assay, or may be apparent in the literature from adiscussion herein that makes a comparison to a factor or substance thatis accepted as an “agonist” or an “antagonist” of the particular bindingpartner under substantially similar circumstances as appreciated bythose of skill in the art. Stimulation may be defined with respect to anincrease in a particular effect or function that is induced byinteraction of the agonist or partial agonist with a binding partner andcan include allosteric effects.

As used herein, an “antagonist” is a substance that inhibits its bindingpartner, typically a receptor. Inhibition is defined in the context ofthe particular assay, or may be apparent in the literature from adiscussion herein that makes a comparison to a factor or substance thatis accepted as an “agonist” or an “antagonist” of the particular bindingpartner under substantially similar circumstances as appreciated bythose of skill in the art. Inhibition may be defined with respect to adecrease in a particular effect or function that is induced byinteraction of the antagonist with a binding partner, and can includeallosteric effects.

As used herein, a “partial agonist” or a “partial antagonist” is asubstance that provides a level of stimulation or inhibition,respectively, to its binding partner that is not fully or completelyagonistic or antagonistic, respectively. It will be recognized thatstimulation, and hence, inhibition is defined intrinsically for anysubstance or category of substances to be defined as agonists,antagonists, or partial agonists.

As used herein, “intrinsic activity” or “efficacy” relates to somemeasure of biological effectiveness of the binding partner complex. Withregard to receptor pharmacology, the context in which intrinsic activityor efficacy should be defined will depend on the context of the bindingpartner (e.g., receptor/ligand) complex and the consideration of anactivity relevant to a particular biological outcome. For example, insome circumstances, intrinsic activity may vary depending on theparticular second messenger system involved. Where such contextuallyspecific evaluations are relevant, and how they might be relevant in thecontext of the present invention, will be apparent to one of ordinaryskill in the art.

As used herein, modulation of a receptor includes agonism, partialagonism, antagonism, partial antagonism, or inverse agonism of areceptor.

As will be appreciated by those skilled in the art, when treating aviral infection such as HCV, HBV, or HIV, such treatment may becharacterized in a variety of ways and measured by a variety ofendpoints. The scope of the present invention is intended to encompassall such characterizations.

In one embodiment, the method can be used to induce an immune responseagainst multiple epitopes of a viral infection in a human. Induction ofan immune response against viral infection can be assessed using anytechnique that is known by those of skill in the art for determiningwhether an immune response has occurred. Suitable methods of detectingan immune response for the present invention include, among others,detecting a decrease in viral load or antigen in a subject's serum,detection of IFN-gamma-secreting peptide specific T cells, and detectionof elevated levels of one or more liver enzymes, such as alaninetransferase (ALT) and aspartate transferase (AST). In one embodiment,the detection of IFN-gamma-secreting peptide specific T cells isaccomplished using an ELISPOT assay. Another embodiment includesreducing the viral load associated with HBV infection, including areduction as measured by PCR testing.

Additionally, the compounds of this invention are useful in thetreatment of cancer or tumors (including dysplasias, such as uterinedysplasia). These includes hematological malignancies, oral carcinomas(for example of the lip, tongue or pharynx), digestive organs (forexample esophagus, stomach, small intestine, colon, large intestine, orrectum), liver and biliary passages, pancreas, respiratory system suchas larynx or lung (small cell and non-small cell), bone, connectivetissue, skin (e.g., melanoma), breast, reproductive organs (uterus,cervix, testicles, ovary, or prostate), urinary tract (e.g., bladder orkidney), brain and endocrine glands such as the thyroid. In summary, thecompounds of this invention are employed to treat any neoplasm,including not only hematologic malignancies but also solid tumors of allkinds.

Hematological malignancies are broadly defined as proliferativedisorders of blood cells and/or their progenitors, in which these cellsproliferate in an uncontrolled manner. Anatomically, the hematologicmalignancies are divided into two primary groups: lymphomas—malignantmasses of lymphoid cells, primarily but not exclusively in lymph nodes,and leukemias—neoplasm derived typically from lymphoid or myeloid cellsand primarily affecting the bone marrow and peripheral blood. Thelymphomas can be sub-divided into Hodgkin's Disease and Non-Hodgkin'slymphoma (NHL). The later group comprises several distinct entities,which can be distinguished clinically (e.g. aggressive lymphoma,indolent lymphoma), histologically (e.g. follicular lymphoma, mantlecell lymphoma) or based on the origin of the malignant cell (e.g. Blymphocyte, T lymphocyte). Leukemias and related malignancies includeacute myelogenous leukemia (AML), chronic myelogenous leukemia (CML),acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia(CLL). Other hematological malignancies include the plasma celldyscrasias including multiple myeloma, and the myelodysplasticsyndromes.

SYNTHETIC EXAMPLES

To a solution of 2-amino-4,6-dichloropyridine (1) (3.26 g, 20.0 mmol) in1-butanol (10 mL) and DMF (1 mL) was added a solution of sodium butoxide(22.0 mL, 1.0 M solution in butanol). The reaction mixture was heated inthe microwave at 130° C. for 45 min and was then poured onto a saturatedsolution of NH₄Cl (50 mL) and EtOAc (50 mL). The layers were separated,and the organic layer was washed with brine (30 mL). The organic layerwas dried, filtered, and concentrated in vacuo. The crude oil waspurified by flash column chromatography (CH₂Cl₂/EtOAc) to give 1.9 g of2.

2: ¹H-NMR: 300 MHz, (CDCl₃) d: 6.11 (s, 1H), 6.07 (s, 1H), 4.40 (br s,2H), 4.17 (t, 2H, J=7 Hz), 1.72 (m, 2H, J=7 Hz), 1.47 (m, 2H, J=7 Hz),0.97 (t, 3H, J=7 Hz).

LCMS-ESI⁺: calc'd for C₉H₁₄ClN₂O: 201.1 (M+H⁺); Found: 201.0 (M+H).

To a solution of aminopyridine 2 (2.15 g, 107 mmol) in H₂SO₄ (27 mL) at−10° C. was added HNO₃ (536 μL, 10.7 mmol) dropwise. The reactionmixture was stirred at −10° C. for 1 h then poured slowly onto ice. Themixture was extracted with EtOAc (50 mL), and the organic layer waswashed with brine (25 mL). The organic layer was dried, filtered, andconcentrated in vacuo. The crude oil was purified by flash columnchromatography (CH₂Cl₂/EtOAc) to give 2.08 g of 3.

3: ¹H-NMR: 300 MHz, (CDCl₃) d: 6.51 (br s, 2H), 6.25 (s, 1H), 4.27 (t,2H, J=7 Hz), 1.72 (m, 2H, J=7 Hz), 1.46 (m, 2H, J=7 Hz), 0.97 (t, 3H,J=7 Hz).

LCMS-ESI⁺: calc'd for C₉H₁₃ClN₃O₃: 246.1 (M+H⁺); Found: 246.0 (M+H).

To a solution of chloropyridine 3 (50 mg, 0.20 mmol) in DMF (2 mL) wasadded Et₃N (100 μL) and amine 4 (75 mg, 0.27 mmol). The reaction mixturewas heated at 80° C. for 14 h. The mixture was poured onto a saturatedsolution of NH₄Cl (10 mL) and EtOAc (10 mL). The layers were separated,and the aqueous layer was extracted with EtOAc (10 mL). The combinedorganic layers were dried, filtered, and concentrated in vacuo. Thecrude product was purified by reverse phase HPLC (MeCN/H₂O containing0.1% TFA). The product was lyophilized to give 16 mg of 5 (TFA salt).

5: ¹H-NMR: 300 MHz, (CD₃OD) d: 7.24-7.38 (m, 4H), 5.55 (s, 1H), 4.59 (s,2H), 4.18 (m, 4H), 3.88 (s, 2H), 3.67 (s, 2H), 2.56 (m, 4H), 1.79 (m,4H), 1.67 (m, 2H, J=7 Hz), 1.41 (m, 2H, J=7 Hz), 1.24 (t, 3H, J=7 Hz),0.95 (t, 3H, J=7 Hz).

LCMS-ESI⁺: calc'd for C₂₅H₃₆N₅O₅: 486.6 (M+H⁺); Found: 486.2 (M+H).

To a solution of nitropyridine 5 (16 mg) in MeOH (3 mL) was added RaneyNi slurry (50 μL). The reaction mixture was stirred under a H₂atmosphere for 1.5 h and was then filtered through a pad of celite withCH₂Cl₂ and MeOH (3:1). The filtrate was concentrated. Then H₂O (1 mL)and a 0.25 M HCl solution (˜300 μL) were added. The mixture was frozenand lyophilized to give 12 mg of A (2HCl salt).

A: ¹H-NMR: 300 MHz, (CD₃OD) d: 7.44-7.60 (m, 4H), 5.93 (s, 1H), 4.83 (s,2H), 4.40 (s, 2H), 4.12 (m, 4H), 3.48 (m, 2H), 3.17 (m, 2H), 2.17 (m,2H), 2.04 (m, 2H), 1.73 (m, 2H, J=7 Hz), 1.45 (m, 2H, J=7 Hz), 0.96 (t,3H, J=7 Hz).

LCMS-ESI⁺: calc'd for C₂₃H₃₂N₅O₂: 410.5 (M+H⁺); Found: 410.1 (M+H).

Synthesized from compound 3 according to the procedure for 5 using ethyl2-(4-(pyrrolidin-1-ylmethyl)benzylamino)acetate.

6: ¹H-NMR: 300 MHz, (CD₃OD) d: 7.31-7.38 (m, 4H), 5.55 (s, 1H), 4.57 (s,2H), 4.16 (m, 4H), 3.86 (s, 2H), 3.69 (s, 2H), 2.62 (m, 4H), 1.83 (m,4H), 1.65 (m, 2H, J=7 Hz), 1.41 (m, 2H, J=7 Hz), 1.23 (t, 3H, J=7 Hz),0.94 (t, 3H, J=7 Hz).

LCMS-ESI⁺: calc'd for C₂₅H₃₆N₅O₅: 486.6 (M+H⁺); Found: 486.1 (M+H).

Synthesized from compound 6 according to the procedure for A.

B: ¹H-NMR: 300 MHz, (CD₃OD) d: 7.62 (d, 2H, J=8 Hz), 7.46 (d, 2H, J=8Hz), 5.96 (s, 1H), 4.82 (s, 2H), 4.41 (s, 2H), 4.12 (m, 4H), 3.49 (m,2H), 3.19 (m, 2H), 2.18 (m, 2H), 2.03 (m, 2H), 1.74 (m, 2H, J=7 Hz),1.46 (m, 2H, J=7 Hz), 0.96 (t, 3H, J=7 Hz).

LCMS-ESI⁺: calc'd for C₂₃H₃₂N₅O₂: 410.5 (M+H⁺); Found: 410.1 (M+H).

Synthesized from 1 according to the procedure for 2.

7: ¹H-NMR: 300 MHz, (CDCl₃) d: 6.17 (s, 1H), 6.07 (s, 1H), 4.37 (br m,4H), 3.70 (t, 2H, J=5 Hz), 3.42 (s, 3H).

LCMS-ESI⁺: calc'd for C₈H₁₂ClN₂O₂: 203.1 (M+H⁺); Found: 203.0 (M+H).

Synthesized from 7 according to the procedure for 3.

8: ¹H-NMR: 300 MHz, (CDCl₃) d: 6.50 (br s, 2H), 6.32 (s, 1H), 4.45 (t,2H, J=5 Hz), 3.70 (t, 2H, J=5 Hz), 3.43 (s, 3H).

LCMS-ESI⁺: calc'd for C₈H₁₁ClN₃O₄: 248.6 (M+H⁺); Found: 248.0 (M+H).

Synthesized from compound 8 according to the procedure for 5 using ethyl2-(4-(pyrrolidin-1-ylmethyl)benzylamino)acetate.

9: ¹H-NMR: 300 MHz, (CD₃OD) d: 7.29-7.39 (m, 4H), 5.60 (s, 1H), 4.57 (s,2H), 4.35 (t, 2H, J=5 Hz), 4.16 (q, 2H, J=7 Hz), 3.86 (s, 2H), 3.68 (m,4H), 3.40 (s, 3H), 2.56 (m, 4H), 1.81 (m, 4H), 1.24 (t, 3H, J=7 Hz).

LCMS-ESI⁺: calc'd for C₂₄H₃₄N₅O₆: 488.6 (M+H⁺); Found: 488.1 (M+H).

Synthesized from compound 9 according to the procedure for A.

C: ¹H-NMR: 300 MHz, (CD₃OD) d: 7.61 (d, 2H, J=8 Hz), 7.46 (d, 2H, J=8Hz), 6.03 (s, 1H), 4.82 (s, 2H), 4.40 (s, 2H), 4.25 (m, 2H), 4.10 (s,2H), 3.70 (m, 2H), 3.48 (m, 2H), 3.36 (s, 3H), 3.19 (m, 2H), 2.17 (m,2H), 2.04 (m, 2H).

LCMS-ESI⁺: calc'd for C₂₃H₃₂N₅O₂: 410.5 (M+H⁺); Found: 410.1 (M+H).

To a solution of 8 (991 mg, 4.00 mmol) in MeCN (16 mL) and acetic acid(2 mL) was added N-chlorosuccinimide (NCS) (641 mg, 4.80 mmol). Thereaction mixture was heated at 85° C. for 5 h and then poured onto H₂O(20 mL) and EtOAc (20 mL). The layers were separated, and the organiclayer was washed with a saturated solution of NaHCO₃ (10 mL). Theorganic layer was dried, filtered, and concentrated in vacuo. The crudeproduct was purified by flash column chromatography (CH₂Cl₂/EtOAc) togive 725 mg of 10.

10: ¹H-NMR: 300 MHz, (CDCl₃) d: 6.33 (br s, 2H), 4.53 (t, 2H, J=5 Hz),3.77 (t, 2H, J=5 Hz), 3.45 (s, 3H).

LCMS-ESI⁺: calc'd for C₈H₁₀Cl₂N₃O₄: 282.0 (M+H⁺); Found: 281.9 (M+H).

Synthesized from compound 10 according to the procedure for 5 usingethyl 2-(4-(pyrrolidin-1-ylmethyl)benzylamino)acetate at 95° C. for 3 h.

9: ¹H-NMR: 300 MHz, (CD₃OD) d: 7.31 (d, 2H, J=8 Hz), 7.23 (d, 2H, J=8Hz), 4.44 (m, 2H), 4.35 (s, 2H), 4.18 (q, 2H, J=7 Hz), 3.92 (s, 2H),3.73 (m, 2H), 3.63 (s, 2H), 3.42 (s, 3H), 2.56 (m, 4H), 1.81 (m, 4H),1.27 (t, 3H, J=7 Hz).

LCMS-ESI⁺: calc'd for C₂₄H₃₃ClN₅O₆: 522.2 (M+H⁺); Found: 522.0 (M+H).

To a solution of nitropyridine 11 (25 mg) in HOAc (1 mL) was added Zn inportions until all 11 was consumed (˜150 mg total). The reaction mixturewas filtered and concentrated in vacua. Then H₂O (1 mL) and a 0.25 M HClsolution (˜500 μL) were added. The mixture was frozen and lyophilized togive 12 mg of A (2HCl salt).

D: ¹H-NMR: 300 MHz, (CD₃OD) d: 7.49 (d, 2H, J=8 Hz), 7.42 (d, 2H, J=8Hz), 4.40 (m, 6H), 3.74 (m, 2H), 3.60 (s, 2H), 3.43 (s, 3H), 3.36 (m,4H), 2.10 (m, 2H).

LCMS-ESI⁺: calc'd for C₂₂H₂₉ClN₅O₃: 446.2 (M+H⁺); Found: 446.0 (M+H).

To a solution of 3 (675 mg, 2.75 mmol) in THF (11 mL) was added Et₃N(1.15 mL, 8.24 mmol), di-tert-butyl dicarbonate (Boc₂O) (1.80 g, 8.24mmol), and DMAP (17 mg, 0.14 mmol). The reaction mixture was stirred atrt for 2.5 h and was then poured onto a saturated solution of NH₄Cl (20mL). The layers were separated, and the aqueous layer was extracted withEtOAc (15 mL). The combined organic layers were dried, filtered, andconcentrated in vacua. The crude product was purified by flash columnchromatography (EtOAc/Hex) to give 1.17 g of 12.

12: ¹H-NMR: 300 MHz, (CDCl₃) d: 6.86 (s, 1H), 4.34 (t, 2H, J=7 Hz), 1.75(m, 2H, J=7 Hz), 1.46 (m, 2H), 1.44 (s, 18H), 0.97 (t, 3H, J=7 Hz).

LCMS-ESI⁺: calc'd for C₁₉H₂₉ClN₃O₇: 446.9 (M+H⁺); Found: 446.2 (M+H).

To a solution of 12 (400 mg, 0.90 mmol) in THF (5 mL) was added Et₃N (1mL) and 13 (190 mg, 1.0 mmol). The reaction mixture was stirred at 50°C. for 1 h. A saturated solution of NH₄Cl (10 mL) was added. The layerswere separated, and the aqueous layer was extracted with EtOAc (15 mL).The combined organic layers were dried, filtered, and concentrated invacua. The crude product was purified by flash column chromatography(CH₂Cl₂/MeOH) to give 302 mg of 14.

14: ¹H-NMR: 300 MHz, (CDCl₃) d: 7.35 (d, 2H, J=8 Hz), 7.25 (d, 2H, J=8Hz), 5.96 (s, 1H), 4.42 (br s, 2H), 4.26 (t, 2H, J=7 Hz), 3.65 (s, 2H),2.55 (br m, 4H), 1.81 (br m, 4H), 1.72 (m, 2H, J=7 Hz), 1.45 (m, 20H),0.94 (t, 3H, J=7 Hz).

LCMS-ESI⁺: calc'd for C₃₁H₄₆N₅O₇: 600.7 (M+H⁺); Found: 600.1 (M+H).

To a solution of nitro 14 (300 mg, 0.5 mmol) in THF, EtOH, and H₂O(1:1:1, 10 mL total) at 60° C. was added Na₂S₂O₄ in portions until all14 was consumed (˜300 mg total). The reaction mixture was poured ontoH₂O (10 mL) and EtOAc (10 mL). The layers were separated, and theaqueous layer was extracted with EtOAc (10 mL). The combined organiclayers were dried, filtered, and concentrated in vacuo. CH₂Cl₂ was added(10 mL) followed by Et₃N (500 μL) and a solution of oxalyl chloride (750μL, 1.0 M solution in CH₂Cl₂). After 2 h, trifluoroacetic acid (TFA) (2mL) was added. The reaction mixture was stirred at rt for 16 h and wasthen poured onto a 2 M solution of NaOH (10 mL). The layers wereseparated, and the aqueous layer was extracted with CH₂Cl₂ (10 mL). Thecombined organic layers were dried, filtered, and concentrated in vacuo.The crude product was purified by reverse phase chromatography (MeCN/H₂Owith 0.1% HCl) to give 5.7 mg of E (2HCl salt).

14: ¹H-NMR: 300 MHz, (CD₃OD) d: 7.54 (d, 2H, J=8 Hz), 7.47 (d, 2H, J=8Hz), 6.10 (s, 1H), 5.52 (s, 2H), 4.37 (s, 2H), 4.14 (t, 2H, J=7 Hz),3.48 (br m, 2H), 3.20 (br m, 2H), 2.18 for m, 2H), 2.02 (br m, 2H), 1.72(m, 2H), 1.46 (m, 2H), 0.95 (t, 3H, J=7 Hz).

LCMS-ESI⁺: calc'd for C₂₃H₃₀N₅O₃: 424.5 (M+H⁺); Found: 424.1 (M+H).

To a solution of aryl bromide 15 (HCl salt, 100 mg, 0.45 mmol) andboronic ester 16 (130 mg, 0.45 mmol) in PhCH₃, EtOH, and H₂O (2:1:1, 4mL total) was added K₂CO₃ (186 mg, 1.3 mmol) and PdCl₂dppf (16 mg, 0.023mmol). The reaction mixture was stirred at 90° C. for 1.5 h. Aftercooling to rt, the mixture was diluted with H₂O (10 mL) and EtOAc (10mL). The layers were separated, and the aqueous layer was extracted withEtOAc (4×10 mL). The combined organic layers were concentrated in vacuaand purified by reverse phase chromatography (MeCN/H₂O containing 0.1%TFA) to give 120 mg of 17.

17: ¹H-NMR: 300 MHz, (CD₃OD) d: 7.75-7.84 (m, 4H), 7.54-7.61 (m, 4H),4.45 (s, 2H), 4.15 (s, 2H), 3.35 (m, 4H), 2.11 (m, 4H).

LCMS-ESI⁺: calc'd for C₁₈H₂₃N₂: 267.4 (M+H⁺); Found: 267.1 (M+H).

Synthesized according to the procedure for 14 using 17.

18: ¹H-NMR: 300 MHz, (CDCl₃) d: 7.88 (m, 1H), 7.62 (d, 2H, J=8 Hz), 7.50(m, 1H), 7.40 (m, 4H), 5.99 (s, 1H), 4.49 (d, 2H, J=5 Hz), 4.34 (m, 2H),3.76 (s, 2H), 2.64 (m, 4H), 1.84 (m, 4H), 1.74 (m, 2H), 1.48 (m, 20H),0.96 (t, 3H, J=7 Hz).

LCMS-ESI⁺: calc'd for C₃₇H₅₀N₅O₇: 676.8 (M+H⁺); Found: 676.2 (M+H).

Synthesized according to the procedure for E using 18.

F: ¹H-NMR: 300 MHz, (CDCl₃) d: 7.70-7.84 (m, 4H), 7.46-7.59 (m, 4H),6.17 (s, 1H), 5.55 (s, 2H), 4.45 (s, 2H), 4.16 (t, 2H, J=7 Hz), 3.53 (m,2H), 3.27 (m, 2H), 2.20 (m, 2H), 2.04 (m, 2H), 1.71 (m, 2H), 1.42 (m,2H), 0.92 (t, 3H, J=7 Hz).

LCMS-ESI⁺: calc'd for C₂₉H₃₄N₅O₃: 500.6 (M+H⁺); Found: 500.1 (M+H).\

Synthesized according to the procedure for 17 using1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidine.

19: ¹H-NMR: 300 MHz, (CD₃OD) d: 7.76-7.79 (m, 4H), 7.56-7.63 (m, 4H),4.43 (s, 2H), 4.18 (s, 2H), 3.54 (m, 2H), 3.24 (m, 2H), 2.21 (m, 2H),2.04 (m, 2H).

LCMS-ESI⁺: calc'd for C₁₈H₂₃N₂: 267.4 (M+H⁺); Found: 267.1 (M+H).

Synthesized according to the procedure for 14 using 19.

20: ¹H-NMR: 300 MHz, (CDCl₃) d: 7.37-7.61 (m, 8H), 5.99 (s, 1H), 4.49(d, 2H, J=5 Hz), 4.27 (m, 2H), 3.76 (s, 2H), 2.66 (m, 4H), 1.87 (m, 4H),1.72 (m, 2H), 1.46 (m, 20H), 0.94 (t, 3H, J=7 Hz).

LCMS-ESI⁺: calc'd for C₃₇H₅₀N₅O₇: 676.8 (M+H⁺); Found: 676.1 (M+H).

Synthesized according to the procedure for E using 18.

G: ¹H-NMR: 300 MHz, (CDCl₃) d: 7.74 (d, 2H, J=8 Hz), 7.68 (d, 2H, J=8Hz), 7.61 (d, 2H, J=8 Hz), 7.46 (d, 2H, J=8 Hz), 6.16 (s, 1H), 5.54 (s,2H), 4.42 (s, 2H), 4.16 (t, 2H, J=7 Hz), 3.52 (m, 2H), 3.24 (m, 2H),2.20 (m, 2H), 2.04 (m, 2H), 1.69 (m, 2H), 1.42 (m, 2H), 0.91 (t, 3H, J=7Hz).

LCMS-ESI⁺: calc'd for C₂₉H₃₄N₅O₃: 500.6 (M+H⁺); Found: 500.1 (M+H).

Prophetic Examples

The following compounds may be synthesized using analogous techniques:

Biological Examples PBMC Assay Protocol

Assays were conducted to determine cytokine stimulation at 24 hours fromhuman Peripheral Blood Mononuclear Cell (PMBC) using the compounds ofthe present invention. The assays were run in duplicate, with 8-point,half-log dilution curves. The compounds of the present invention werediluted from 10 mM DMSO solution. Cell supernatants are assayed directlyfor IFNa and 1:10 dilution for TNFa. The assays were performed in asimilar fashion as described in Bioorg. Med. Chem. Lett. 16, 4559,(2006). Specifically, cryo-preserved PBMCs were thawed and seeded 96well plates with 750,000 cells/well in 190 μL/well cell media. The PBMCswere then incubated for 1 hour at 37° C. at 5% CO2. Then, the compoundsof the present invention were added in 10 μL cell media at 8 point,half-log dilution titration. The plates were incubated at 37° C. and 5%CO2 for 24 hours and then spinned at 1200 rpm for 10 min, which wasfollowed by collecting supernatant and storing the same at −80° C.Cytokine secretion was assayed with Luminex and Upstate multi-plex kits,using a Luminex analysis instrument. IFN ECmax value for a compound wasthe concentration at which the compound stimulated maximum IFN-aproduction as determined using the assay method above.

Table 1 shows the MEC values for Compounds A-G of the present invention.

TABLE 1 Example MEC A d B c C a D e E b F c G c MEC = minimumconcentration for induction of IFN-alpha = 3-fold over background a: = 1nM b: 1 nM-9 nM c: 10 nM-99 nM d: 100 nM-1000 nM e: = 1000 nM

The specific pharmacological responses observed may vary according toand depending on the particular active compound selected or whetherthere are present pharmaceutical carriers, as well as the type offormulation and mode of administration employed, and such expectedvariations or differences in the results are contemplated in accordancewith practice of the present invention.

Although specific embodiments of the present invention are hereinillustrated and described in detail, the invention is not limitedthereto. The above detailed descriptions are provided as exemplary ofthe present invention and should not be construed as constituting anylimitation of the invention. Modifications will be obvious to thoseskilled in the art, and all modifications that do not depart from thespirit of the invention are intended to be included with the scope ofthe appended claims.

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: L¹ is —NR⁸—,—O—, —S—, —N(R⁸)C(O)—, —S(O)₂—, —S(O)—, or a covalent bond; R¹ is H,alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl,carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substitutedcarbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl,heteroarylalkyl, substituted heteroarylalkyl, carbocyclylalkenyl,substituted carbocyclylalkenyl, carbocyclylalkynyl, substitutedcarbocyclylalkynyl, heterocyclylalkenyl, substitutedheterocyclylalkenyl, heterocyclylalkylyl, substituted heteroalkylyl,arylalkenyl, substituted arylalkenyl, arylalkynyl, substitutedarylalkynyl, heteroarylalkenyl, substituted heteroarylalkenyl,heteroarylalkylyl, substituted heteroarylalkynyl,carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl,heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl,arylheteroalkyl, substituted arylheteroalkyl, heteroarylheteroalkyl, orsubstituted heteroarylheteroalkyl; Z is H, halogen, alkyl, substitutedalkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substitutedcarbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclylalkyl, or substitutedheterocyclylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl,substituted heteroarylalkyl, carbocyclylheteroalkyl, substitutedcarbocyclylheteroalkyl, heterocyclylheteroalkyl, substitutedheterocyclylheteroalkyl, arylheteroalkyl, substituted arylheteroalkyl,heteroarylheteroalkyl, or substituted heteroarylheteroalkyl, cyano,azido, —C(O)H, —C(O)R⁸, —S(O)R⁸, —S(O)₂R⁸, —S(O)₂NR⁸R⁹, —C(O)OR⁸, or—C(O)NR⁹R¹⁰; each non-hydrogen Z may connect to X¹ to form an additional5 to 8 membered carbocyclic or heterocyclic ring; X¹ is alkylene,substituted alkylene, heteroalkylene, substituted heteroalkylene,alkenylene, substituted alkenylene, alkynylene, substituted alkynylene,carbocyclylene, substituted carbocyclylene, heterocyclylene, substitutedheterocyclylene, —NR⁸—, —O—, —C(O)—, —S(O)—, —S(O)₂—, or a covalentbond; D is carbocyclyl, heterocyclyl, aryl, or heteroaryl, bearing anopen valence for the attachment points of each R³ and (L²-R²); each L²is independently alkylene, substituted alkylene, heteroalkylene,substituted heteroalkylene, alkenylene, substituted alkenylene,alkynylene, substituted alkynylene, carbocycylene, substitutedcarbocyclylene, heterocyclylene, substituted heterocyclylene, arylene,substituted arylene, heteroarylene, substituted heteroarylene,arylene-alkylene, heteroarylene-alkylene, arylene-heteroalkylene,substituted arylene-heteroalkylene, heteroarylene-heteroalkylene,substituted heteroarylene-heteroalkylene, or a covalent bond; each R² isindependently —NR⁶R⁷; m is 1 or 2; each R³ is independently alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, halogen, haloalkyl, haloalkoxy, heteroalkyl, substitutedheteroalkyl, ═O, —OR⁸, —SR⁸, —NR⁹R¹⁰, ═NR⁸, ═NOR⁸, ═NNR⁸R⁹, —CN, —OCN,—SCN, —N═C═O, —NCS, —NO, —NO₂, ═N₂, —N₃, —NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹,—NR⁸C(═O)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)OR⁸, —OC(═O)NR⁹R¹⁰, —OC(═O)OR⁸,C(═O)R⁸, —S(═O)₂OR⁸, —S(═O)₂R⁸, —OS(═O)₂OR⁸, —S(═O)₂NR⁹R¹⁰, —S(═O)R⁸,—NR⁸S(═O)₂R⁹, —NR⁸S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂OR⁹, —OS(O)₂NR⁹R¹⁰,—OP(═O)(OR⁸)₂, —P(═O)(OR⁸)₂, —P(O)(OR⁸)(R⁹), —P(O)R⁹R¹⁰, —OP(═))R⁹R¹⁰,—C(═S)R⁸, —C(═S)OR⁸, —C(═O)SR⁸, —C(═S)NR⁹R¹⁰, —C(═NR⁸)NR⁹R¹⁰, or—NR⁸C(═NR⁸)NR⁹R¹⁰; n is 0, 1, 2, 3, 4 or 5, depending on the size of thedepicted ring D, such that sufficient attachment points are present; R⁴and R⁵ are each independently H, alkyl, substituted alkyl, haloalkyl,heteroalkyl, substituted heteroalkyl, carbocyclyl, substitutedcarbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclylalkyl, substitutedheterocyclylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl,carbocyclylalkenyl, substituted carbocyclylalkenyl, carbocyclylalkynyl,substituted carbocyclylalkynyl, heterocyclylalkenyl, substitutedheterocyclylalkenyl, heterocyclylalkylyl, substituted heteroalkylyl,arylalkenyl, substituted arylalkenyl, arylalkynyl, substitutedarylalkynyl, heteroarylalkenyl, substituted heteroarylalkenyl,heteroarylalkylyl, substituted heteroarylalkynyl, substitutedheteroarylalkyl, carbocyclylheteroalkyl, substitutedcarbocyclylheteroalkyl, heterocyclyl heteroalkyl, substitutedheterocyclyl heteroalkyl, arylheteroalkyl, substituted arylheteroalkyl,heteroarylheteroalkyl, or substituted heteroarylheteroalkyl, cyano,azido, —OH, alkoxy, —C(O)H, —C(O)R⁸, —SR⁸, —S(O)R⁸, —S(O)₂R⁸, —C(O)OR⁸,or —C(O)NR⁹R¹⁰; or R⁴ and R⁵, taken together with the carbon to whichthey are both attached, form a substituted or unsubstituted 3 to 8membered carbocycle or heterocycle; or R⁴ and R⁵, taken together withthe carbon to which they are attached, form a —C(═O), —C(═NR⁸),—C(═NOR⁸), or —C(═NNR⁸R⁹); R⁶ and R⁷ are each independently H, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, haloalkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl,substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl,heterocyclyl, substituted heterocyclyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclylalkyl, substitutedheterocyclylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl,carbocyclylalkenyl, substituted carbocyclylalkenyl, carbocyclylalkynyl,substituted carbocyclylalkynyl, heterocyclylalkenyl, substitutedheterocyclylalkenyl, heterocyclylalkylyl, substituted heteroalkylyl,arylalkenyl, substituted arylalkenyl, arylalkynyl, substitutedarylalkynyl, heteroarylalkenyl, substituted heteroarylalkenyl,heteroarylalkylyl, substituted heteroarylalkynyl, substitutedheteroarylalkyl carbocyclylheteroalkyl, substitutedcarbocyclylheteroalkyl, heterocyclylheteroalkyl, substitutedheterocyclylheteroalkyl, arylheteroalkyl, substituted arylheteroalkyl,heteroarylheteroalkyl, or substituted heteroarylheteroalkyl, —C(O)H,—C(O)R⁸, —S(O)R⁸, —S(O)₂R⁸, —C(O)OR⁸, or —C(O)NR⁹R¹⁰, S(O)₂NR⁹R¹⁰; or R⁶and R⁷, taken together with the nitrogen to which they are bothattached, form a substituted or unsubstituted 3 to 8 memberedheterocycle, which may contain one or more additional heteroatomsselected from N, O, S, or P; or R⁷ taken together with L², and the N towhich they are both attached, forms a substituted or unsubstituted 3 to8 membered heterocycle which may contain one or more additionalheteroatoms selected from N, O, S, or P; or R⁷ taken together with D,L², and the N to which both R⁷ and L² are attached forms a substitutedor unsubstituted 5 to 15 membered heterocycle or heteroaryl which maycontain one or more additional heteroatoms selected from N, O, S, or P;R⁸ is H, alkyl, substituted alkyl, haloalkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, heteroalkyl, substitutedheteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl,substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclylalkyl, substituted heterocyclylalkyl, arylalkyl, substitutedarylalkyl, heteroarylalkyl, substituted heteroarylalkyl,carbocyclylalkenyl, substituted carbocyclylalkenyl, carbocyclylalkynyl,substituted carbocyclylalkynyl, heterocyclylalkenyl, substitutedheterocyclylalkenyl, heterocyclylalkylyl, substituted heteroalkylyl,arylalkenyl, substituted arylalkenyl, arylalkynyl, substitutedarylalkynyl, heteroarylalkenyl, substituted heteroarylalkenyl,heteroarylalkylyl, substituted heteroarylalkynyl,carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl,heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl,arylheteroalkyl, substituted arylheteroalkyl, heteroarylheteroalkyl, orsubstituted heteroarylheteroalkyl; and R⁹ and R¹⁰ are each independentlyH, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, haloalkyl, heteroalkyl, substituted heteroalkyl,carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substitutedcarbocyclylalkyl, heterocyclyl, substituted heterocyclyl,heterocyclylalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, substituted heterocyclylalkyl, arylalkyl, substitutedarylalkyl, heteroarylalkyl, substituted heteroarylalkyl,carbocyclylalkenyl, substituted carbocyclylalkenyl, carbocyclylalkynyl,substituted carbocyclylalkynyl, heterocyclylalkenyl, substitutedheterocyclylalkenyl, heterocyclylalkylyl, substituted heteroalkylyl,arylalkenyl, substituted arylalkenyl, arylalkynyl, substitutedarylalkynyl, heteroarylalkenyl, substituted heteroarylalkenyl,heteroarylalkylyl, substituted heteroarylalkynyl,carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl,heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl,arylheteroalkyl, substituted arylheteroalkyl, heteroaryl heteroalkyl, orsubstituted heteroarylheteroalkyl; or R⁹ and R¹⁰, taken together withthe atom to which they are both attached, form a substituted orunsubstituted 3 to 8 membered heterocycle.
 2. A compound of Formula Ia:

or a pharmaceutically acceptable salt thereof, wherein: L¹ is —NH— or—O—; R¹ is H, alkyl, substituted alkyl, carbocylyl, substitutedcarbocyclyl, heterocyclyl, substituted heterocyclyl, carbocyclylalkyl,substituted carbocyclylalkyl, heterocyclylalkyl, or substitutedheterocycylalkyl; X¹ is alkylene, substituted alkylene, heteroalkylene,or substituted heteroalkylene; D is aryl or heteroaryl; n is 0, 1, or 2;each R³ is independently alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, halogen, haloalkyl, haloalkoxy,heteroalkyl, substituted heteroalkyl, ═O, —OR⁸, —SR⁸, —NR⁹R¹⁰, ═NR⁸,═NOR⁸, ═NNR⁸R⁹, —CN, —OCN, —SCN, —N═C═O, —NCS, —NO, —NO₂, ═N₂, —N₃,—NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)OR⁸,—OC(═O)NR⁹R¹⁰, —OC(═O)OR⁸, —C(═O)R⁸, —S(═O)₂OR⁸, —S(═O)₂R⁸, —OS(═O)₂OR⁸,—S(═O)₂NR⁹R¹⁰, —S(═O)R⁸, —NR⁸S(═O)₂R⁹, —NR⁸S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂OR⁹,—OS(O)₂NR⁹R¹⁰, —OP(═O)(OR⁸)₂, —P(═O)(OR⁸)₂, —P(O)(OR⁸)(R⁹), —P(O)R⁹R¹⁰,—OP(═))R⁹R¹⁰, —C(═S)R⁸, —O(═S)OR⁸, —C(═O)SR⁸, —C(═S)SR⁸, —C(═S)NR⁹R¹⁰,—C(═NR⁸)NR⁹R¹⁰, or —NR⁸C(═NR⁸)NR⁹R¹⁰; m is 1 or 2; R⁴ and R⁵ are eachindependently H, alkyl, substituted alkyl, haloalkyl, heteroalkyl, orsubstituted heteroalkyl; L² is alkylene or heteroalkylene; Z is H,halogen, alkyl, substituted alkyl, haloalkyl, heteroalkyl, substitutedheteroalkyl, cyano, azido, —C(O)H, —C(O)R⁸, —S(O)R⁸, —S(O)₂R⁸,—S(O)₂NR⁸R⁹, —C(O)OR⁸, or —C(O)NR⁹R¹⁰; R² is —NR⁶R⁷; and each of R⁶ andR⁷ independently is H, alkyl, substituted alkyl, heteroalkyl,substituted heteroalkyl, carbocyclyl, substituted carbocyclyl,heterocyclyl, substituted heterocyclyl, carbocylylalkyl, substitutedcarbocyclylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, arylalkyl, substituted arylalkyl,heteroarylalkyl, or substituted heteroarylalkyl; or together with thenitrogen to which they are attached form a substituted or unsubstituted3 to 8 membered heterocyclyl; and R⁸, R⁹, and R¹⁰ are each independentlyH, alkyl, substituted alkyl, haloalkyl, heteroalkyl, substitutedheteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl,substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl,heterocyclylalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, substituted heterocyclylalkyl, arylalkyl, substitutedarylalkyl, heteroarylalkyl, substituted heteroarylalkyl,carbocyclylalkenyl, substituted carbocyclylalkenyl, carbocyclylalkynyl,substituted carbocyclylalkynyl, heterocyclylalkenyl, substitutedheterocyclylalkenyl, heterocyclylalkylyl, substituted heteroalkylyl,arylalkenyl, substituted arylalkenyl, arylalkynyl, substitutedarylalkynyl, heteroarylalkenyl, substituted heteroarylalkenyl,heteroarylalkylyl, substituted heteroarylalkynyl,carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl,heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl,arylheteroalkyl, substituted arylheteroalkyl, heteroarylheteroalkyl, orsubstituted heteroarylheteroalkyl,
 3. A compound of Formula Ib:

or a pharmaceutically acceptable salt thereof, wherein: L¹ is —NH— or—O—; R¹ is H, alkyl, substituted alkyl, carbocylyl, substitutedcarbocyclyl, heterocyclyl, substituted heterocyclyl, carbocyclylalkyl,substituted carbocyclylalkyl, heterocyclylalkyl, or substitutedheterocycylalkyl; X¹ is alkylene, substituted alkylene, heteroalkylene,or substituted heteroalkylene; D is aryl or heteroaryl; n is 0, 1, or 2;each R³ is independently alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, halogen, haloalkyl, haloalkoxy,heteroalkyl, substituted heteroalkyl, ═O, —OR⁸, —SR⁸, —NR⁹R¹⁰, ═NR⁸,═NOR⁸, ═NNR⁸R⁹, —CN, —OCN, —SCN, —N═C═O, —NCS, —NO, —NO₂, ═N₂, —N₃,—NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)OR⁸,—OC(═O)NR⁹R¹⁰, —OC(═O)OR⁸, —C(═O)R⁸, —S(═O)₂OR⁸, —S(═O)₂R⁸, —OS(═O)₂OR⁸,—S(═O)₂NR⁹R¹⁰, —S(═O)R⁸, —NR⁸S(═O)₂R⁹, —NR⁸S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂OR⁹,—OS(O)₂NR⁹R¹⁰, —OP(═O)(OR⁸)₂, —P(═O)(OR⁸)₂, —P(O)(OR⁸)(R⁹), —P(O)R⁹R¹⁰,—OP(═))R⁹R¹⁰, —C(═S)R⁸, —O(═S)OR⁸, —C(═O)SR⁸, —O(═S)SR⁸, —C(═S)NR⁹R¹⁰,—C(═NR⁸)NR⁹R¹⁰, or —NR⁸C(═NR⁸)NR⁹R¹⁰; m is 1 or 2; R⁴ and R⁵ are eachindependently H, alkyl, substituted alkyl, haloalkyl, heteroalkyl, orsubstituted heteroalkyl; L² is alkylene or heteroalkylene; Z is H,halogen, alkyl, substituted alkyl, haloalkyl, heteroalkyl, substitutedheteroalkyl, cyano, azido, —C(O)H, —C(O)R⁸, —S(O)R⁸, —S(O)₂R⁸,—S(O)₂NR⁸R⁹, —C(O)OR⁸, or —C(O)NR⁹R¹⁰; R² is —NR⁶R⁷; R⁶ and R⁷ togetherwith the nitrogen to which they are attached form a substituted orunsubstituted 3 to 8 membered heterocyclyl; and R⁸, R⁹, and R¹⁰ are eachindependently H, alkyl, substituted alkyl, haloalkyl, heteroalkyl,substituted heteroalkyl, carbocyclyl, substituted carbocyclyl,carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl,substituted heterocyclyl, heterocyclylalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, substituted heterocyclylalkyl,arylalkyl, substituted arylalkyl, heteroarylalkyl, substitutedheteroarylalkyl, carbocyclylalkenyl, substituted carbocyclylalkenyl,carbocyclylalkynyl, substituted carbocyclylalkynyl, heterocyclylalkenyl,substituted heterocyclylalkenyl, heterocyclylalkylyl, substitutedheteroalkylyl, arylalkenyl, substituted arylalkenyl, arylalkynyl,substituted arylalkynyl, heteroarylalkenyl, substitutedheteroarylalkenyl, heteroarylalkylyl, substituted heteroarylalkynyl,carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl,heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl,arylheteroalkyl, substituted arylheteroalkyl, heteroarylheteroalkyl, orsubstituted heteroarylheteroalkyl.
 4. A compound of Formula Ic:

or a pharmaceutically acceptable salt thereof, wherein: L¹ is —NH— or—O—; R¹ is H, alkyl, substituted alkyl, carbocylyl, substitutedcarbocyclyl, heterocyclyl, substituted heterocyclyl, carbocyclylalkyl,substituted carbocyclylalkyl, heterocyclylalkyl, or substitutedheterocycylalkyl; X¹ is alkylene, substituted alkylene, heteroalkylene,or substituted heteroalkylene; D is aryl or heteroaryl; n is 0, 1, or 2;each R³ is independently alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, halogen, haloalkyl, haloalkoxy,heteroalkyl, substituted heteroalkyl, ═O, —OR⁸, —SR⁸, —NR⁹R¹⁰, ═NR⁸,═NOR⁸, ═NNR⁸R⁹, —CN, —OCN, —SCN, —N═C═O, —NCS, —NO, —NO₂, ═N₂, —N₃,—NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)OR⁸,—OC(═O)NR⁹R¹⁰, —OC(═O)OR⁸, —C(═O)R⁸, —S(═O)₂OR⁸, —S(═O)₂R⁸, —OS(═O)₂OR⁸,—S(═O)₂NR⁹R¹⁰, —S(═O)R⁸, —NR⁸S(═O)₂R⁹, —NR⁸S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂OR⁹,—OS(O)₂NR⁹R¹⁰, —OP(═O)(OR⁸)₂, —P(═O)(OR⁸)₂, —P(O)(OR⁸)(R⁹), —P(O)R⁹R¹⁰,—OP(═))R⁹R¹⁰, —C(═S)R⁸, —C(═S)OR⁸, —C(═O)SR⁸, —C(═S)SR⁸, —C(═S)NR⁹R¹⁰,—C(═NR⁸)NR⁹R¹⁰, or —NR⁸C(═NR⁸)NR⁹R¹⁰; m is 1 or 2; R⁴ and R⁵ are eachindependently H, alkyl, substituted alkyl, haloalkyl, heteroalkyl, orsubstituted heteroalkyl; L² is alkylene or heteroalkylene; Z is H,halogen, alkyl, substituted alkyl, haloalkyl, heteroalkyl, substitutedheteroalkyl, cyano, azido, —C(O)H, —C(O)R⁸, —S(O)R⁸, —S(O)₂R⁸,—S(O)₂NR⁸R⁹, —C(O)OR⁸, or —C(O)NR⁹R¹⁰; R² is —NR⁶R⁷; and R⁶ is H, alkyl,substituted alkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl,substituted carbocyclyl, heterocyclyl, substituted heterocyclyl,carbocylylalkyl, substituted carbocyclylalkyl, heterocyclylalkyl,substituted heterocyclylalkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, heteroaryl, substituted heteroaryl, arylalkyl,substituted arylalkyl, heteroarylalkyl, or substituted heteroarylalkyl;or together with R⁷ and the nitrogen to which they are attached form asubstituted or unsubstituted 3 to 8 membered heterocyclyl; or R⁷ takentogether with D, L², and the N to which both R⁷ and L² are attachedforms a substituted or unsubstituted 5 to 15 membered heterocycle orheteroaryl which may contain one or more additional heteroatoms selectedfrom N, O, S, or P; and R⁸, R⁹, and R¹⁰ are each independently H, alkyl,substituted alkyl, haloalkyl, heteroalkyl, substituted heteroalkyl,carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substitutedcarbocyclylalkyl, heterocyclyl, substituted heterocyclyl,heterocyclylalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, substituted heterocyclylalkyl, arylalkyl, substitutedarylalkyl, heteroarylalkyl, substituted heteroarylalkyl,carbocyclylalkenyl, substituted carbocyclylalkenyl, carbocyclylalkynyl,substituted carbocyclylalkynyl, heterocyclylalkenyl, substitutedheterocyclylalkenyl, heterocyclylalkylyl, substituted heteroalkylyl,arylalkenyl, substituted arylalkenyl, arylalkynyl, substitutedarylalkynyl, heteroarylalkenyl, substituted heteroarylalkenyl,heteroarylalkylyl, substituted heteroarylalkynyl,carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl,heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl,arylheteroalkyl, substituted arylheteroalkyl, heteroarylheteroalkyl, orsubstituted heteroarylheteroalkyl.
 5. A compound of Formula Id:

or a pharmaceutically acceptable salt thereof, wherein: L¹ is —NH— or—O—; R¹ is H, alkyl, substituted alkyl, carbocylyl, substitutedcarbocyclyl, heterocyclyl, substituted heterocyclyl, carbocyclylalkyl,substituted carbocyclylalkyl, heterocyclylalkyl, or substitutedheterocycylalkyl; X¹ is alkylene, substituted alkylene, heteroalkylene,or substituted heteroalkylene; D is aryl or heteroaryl; n is 0, 1, or 2;each R³ is independently alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, halogen, haloalkyl, haloalkoxy,heteroalkyl, substituted heteroalkyl, ═O, —OR⁸, —SR⁸, —NR⁹R¹⁰, ═NR⁸,═NOR⁸, ═NNR⁸R⁹, —CN, —OCN, —SCN, —N═C═O, —NCS, —NO, —NO₂, ═N₂, —N₃,—NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)OR⁸,—OC(═O)NR⁹R¹⁰, —OC(═O)OR⁸, —C(═O)R⁸, —S(═O)₂OR⁸, —S(═O)₂R⁸, —OS(═O)₂OR⁸,—S(═O)₂NR⁹R¹⁰, —S(═O)R⁸, —NR⁸S(═O)₂R⁹, —NR⁸S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂OR⁹,—OS(O)₂NR⁹R¹⁰, —OP(═O)(OR⁸)₂, —P(═O)(OR⁸)₂, —P(O)(OR⁸)(R⁹), —P(O)R⁹R¹⁰,—OP(═))R⁹R¹⁰, —C(═S)R⁸, —C(═S)OR⁸, —C(═O)SR⁸, —C(═S)SR⁸, —C(═S)NR⁹R¹⁰,—O(═NR⁸)NR⁹R¹⁰, or —NR⁸C(═NR⁸)NR⁹R¹⁰; m is 1 or 2; R⁴ and R⁵ are eachindependently H, alkyl, substituted alkyl, haloalkyl, heteroalkyl, orsubstituted heteroalkyl; L² is arylene-alkylene, heteroarylene-alkylene,arylene-heteroalkylene, or heteroarylene-heteroalkylene, each of whichmay be optionally substituted; Z is H, halogen, alkyl, substitutedalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cyano, azido,—C(O)H, —C(O)R⁸, —S(O)R⁸, —S(O)₂R⁸, —S(O)₂NR⁸R⁹, —C(O)OR⁸, or—C(O)NR⁹R¹⁰; R² is —NR⁶R⁷; each of R⁶ and R⁷ independently is H, alkyl,substituted alkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl,substituted carbocyclyl, heterocyclyl, substituted heterocyclyl,carbocylylalkyl, substituted carbocyclylalkyl, heterocyclylalkyl,substituted heterocyclylalkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, heteroaryl, substituted heteroaryl, arylalkyl,substituted arylalkyl, heteroarylalkyl, or substituted heteroarylalkyl;or together with the nitrogen to which they are attached form asubstituted or unsubstituted 3 to 8 membered heterocyclyl; and R⁸, R⁹,and R¹⁰ are each independently H, alkyl, substituted alkyl, haloalkyl,heteroalkyl, substituted heteroalkyl, carbocyclyl, substitutedcarbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl,heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, substitutedheterocyclylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl,substituted heteroarylalkyl, carbocyclylalkenyl, substitutedcarbocyclylalkenyl, carbocyclylalkynyl, substituted carbocyclylalkynyl,heterocyclylalkenyl, substituted heterocyclylalkenyl,heterocyclylalkylyl, substituted heteroalkylyl, arylalkenyl, substitutedarylalkenyl, arylalkynyl, substituted arylalkynyl, heteroarylalkenyl,substituted heteroarylalkenyl, heteroarylalkylyl, substitutedheteroarylalkynyl, carbocyclyl heteroalkyl, substitutedcarbocyclylheteroalkyl, heterocyclylheteroalkyl, substitutedheterocyclylheteroalkyl, arylheteroalkyl, substituted arylheteroalkyl,heteroarylheteroalkyl, or substituted heteroarylheteroalkyl.
 6. Acompound of Formula Ie:

or a pharmaceutically acceptable salt thereof, wherein; L¹ is —NH— or—O—; R¹ is H, alkyl, substituted alkyl, carbocylyl, substitutedcarbocyclyl, heterocyclyl, substituted heterocyclyl, carbocyclylalkyl,substituted carbocyclylalkyl, heterocyclylalkyl, or substitutedheterocycylalkyl; X¹ is alkylene, substituted alkylene, heteroalkylene,or substituted heteroalkylene; D is aryl or heteroaryl; n is 0, 1, or 2;each R³ is independently alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, halogen, haloalkyl, haloalkoxy,heteroalkyl, substituted heteroalkyl, ═O, —OR⁸, —SR⁸, —NR⁹R¹⁰, ═NR⁸,═NNR⁸R⁹, —CN, —OCN, —SCN, —N═C═O, —NCS, —NO, —NO₂, ═N₂, —N₃,—NR⁸C(═O)R⁹, —NR⁸C(═O)OR⁹, —NR⁸C(═O)NR⁹R¹⁰, —C(═O)NR⁹R¹⁰, —C(═O)OR⁸,—OC(═O)NR⁹R¹⁰, —OC(═O)OR⁸, —C(═O)R⁸, —S(═O)₂OR⁸, —S(═O)₂R⁸, —OS(═O)₂OR⁸,—S(═O)₂NR⁹R¹⁰, —S(═O)R⁸, —NR⁸S(═O)₂R⁹, —NR⁸S(═O)₂NR⁹R¹⁰, —NR⁸S(═O)₂OR⁹,—OS(O)₂NR⁹R¹⁰, —OP(═O)(OR⁸)₂, —P(═O)(OR⁸)₂, —P(O)(OR⁸)(R⁹), —P(O)R⁹R¹⁰,—OP(═))R⁹R¹⁰, —C(═S)R⁸, —C(═S)OR⁸, —C(═O)SR⁸, —C(═S)SR⁸, —C(═S)NR⁹R¹⁰,—C(═NR⁸)NR⁹R¹⁰, or —NR⁸C(═NR⁸)NR⁹R¹⁰; m is 1 or 2; L² is alkylene orheteroalkylene; Z is H, halogen, alkyl, substituted alkyl, haloalkyl,heteroalkyl, substituted heteroalkyl, cyano, azido, —C(O)H, —C(O)R⁸,—S(O)R⁸, —S(O)₂R⁸, —S(O)₂NR⁸R⁹, —C(O)OR⁸, or —C(O)NR⁹R¹⁰; R² is —NR⁶R⁷;each of R⁶ and R⁷ independently is H, alkyl, substituted alkyl,heteroalkyl, substituted heteroalkyl, carbocyclyl, substitutedcarbocyclyl, heterocyclyl, substituted heterocyclyl, carbocylylalkyl,substituted carbocyclylalkyl, heterocyclylalkyl, substitutedheterocyclylalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, arylalkyl, substitutedarylalkyl, heteroarylalkyl, or substituted heteroarylalkyl; or togetherwith the nitrogen to which they are attached form a substituted orunsubstituted 3 to 8 membered heterocyclyl; R⁴ and R⁵ taken togetherwith the carbon to which they are attached form a —C(═O); and R⁸, R⁹,and R¹⁰ are each independently H, alkyl, substituted alkyl, haloalkyl,heteroalkyl, substituted heteroalkyl, carbocyclyl, substitutedcarbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl,heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, substitutedheterocyclylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl,substituted heteroarylalkyl, carbocyclylalkenyl, substitutedcarbocyclylalkenyl, carbocyclylalkynyl, substituted carbocyclylalkynyl,heterocyclylalkenyl, substituted heterocyclylalkenyl,heterocyclylalkylyl, substituted heteroalkylyl, arylalkenyl, substitutedarylalkenyl, arylalkynyl, substituted arylalkynyl, heteroarylalkenyl,substituted heteroarylalkenyl, heteroarylalkylyl, substitutedheteroarylalkynyl, carbocyclylheteroalkyl, substitutedcarbocyclylheteroalkyl, heterocyclylheteroalkyl, substitutedheterocyclylheteroalkyl, arylheteroalkyl, substituted arylheteroalkyl,heteroarylheteroalkyl, or substituted heteroarylheteroalkyl.
 7. Thecompound of any one of claims 1-6, wherein L¹ is oxygen.
 8. The compoundof any one of claims 1-6, wherein X¹ is alkylene.
 9. The compound of anyone of claims 1-6, wherein D is aryl.
 10. The compound of claim 9,wherein D is phenyl.
 11. The compound of any one of claims 1-6, whereinL² is alkylene;
 12. A pharmaceutical composition comprising a compoundaccording to claims 1-6, and one or more pharmaceutically acceptablecarrier or excipient.
 13. The pharmaceutical composition of claim 12,further comprising one or more additional therapeutic agent.
 14. Amethod for treating a viral infection comprising administering acompound according to claims 1-6.
 15. The method of claim 14, whereinthe treatment results in one or more of a reduction in viral load orclearance of viral RNA.